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If the IAVI G001 HIV vaccine proves itself, why would it work?

If the IAVI G001 HIV vaccine proves itself, why would it work?


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The IAVI G001 HIV vaccine trial looks promising.

If it works, will it work by preventing a single cell from being infected, or by allowing the body to attack infected cells?

What I'm trying to understand is if a person living with HIV for years can't develop immunity, why might the vaccine succeed?


"Trojan Horse" Vaccines Could Prevent HIV Infections

BALTIMORE, Md. -- After more than a decade of targeting steps of the AIDS virus entering human cells, a team of vaccine researchers now with the University of Maryland Biotechnology Institute (UMBI), have designed new vaccines to stop HIV infections before they can occur by sex, blood exchange or other means.

The team has received a new $5.3 million grant from the National Institutes of Health (NIH) to help complete the best of their HIV vaccines, according to David M. Hone, associate research professor at UMBI's Institute of Human Virology (IHV).

The IHV vaccines are carried directly into human cells by a strain of Salmonella bacteria that Hone and colleagues have severely crippled by multiple mutations. The vaccine itself, in each case, is a liquid suspension of the nontoxic bacteria, swallowed by volunteers.

The oral vaccines include bits of DNA from HIV's outer coat, which the researchers have also rendered harmless. The bits of HIV cannot cause AIDS. At IHV, the vaccinating system has been tested successfully for safety in human volunteers.

Racing against still-raging AID pandemic around the world, and an ever increasing number of HIV mutations, the team will apply the NIH funding to make sure at least one of their vaccine candidates soon becomes a clinical success. They will begin clinical trials of the best candidates as soon as late this year.

"One of the unique aspects of our trials is that we have a wide array of vaccines coming down the pipeline because we are fully aware that vaccine development is 99 percent misses with the occasionally one vaccine that stands on its merits," explains Hone.

The method of putting a vaccine into Salmonella or another infectious bacteria species-bactofection--has already been approved in part by the U.S. Food and Drug Administration in previous volunteer studies of nontoxic Salmonella carrying DNA that makes a piece of the HIV protein, says Hone.

Principal investigator of the NIH grant George Lewis, who directs IHV's vaccine division, describes bactofection as a "Trojan horse-like" surprise attack on the elusive AIDS virus. "We have altered the Salmonella so it can no longer cause any intestinal illness, but the bacteria still know all the roadmaps to get inside human cells. The cells themselves use the piece of HIV DNA delivered by the bacteria to then manufacture copies of the HIV antigen."

Four and a half years ago, three independent groups of researchers, including a University of Maryland team at IHV, discovered that certain bacteria could transfect or move bits of DNA into cells of higher organisms and have the DNA express or manufacture the new copies in the cells. The IHV team gained two broad U.S. patents for the system, one in 1999, and one in 2000.

Lewis says that in practical terms of fighting AIDS globally, a vaccine locked into Salmonella bacteria is "extremely transportable." It may not need refrigeration in developing countries. It would also be far less expensive to manufacture than other AIDS vaccines under development, according to Seth Berkeley, president of the International AIDS Vaccine Initiative. The non-profit IAVI, in July pledged to help develop the IHV vaccine delivery system in Africa. The oral vaccines also eliminate the need for sterile needles, meeting a requirement of the World Health Organization for AIDS vaccines.

Biologically, the innovative IHV vaccines provide protection both by whole body immunity as well as in the critically important mucosal tissues, such as the genito-urinary tract and rectum, where HIV often first enters the body during sexual contact with an HIV infected individual. So far, the vaccines have been shown in animals to induce strong reactions by mucosal immune cells that are similar to those known by researchers to stop HIV infection. At the same time, the vaccines also stimulate a strong immune reaction to fight HIV in the blood stream, says Hone.

"If this proves to be both safe and very immunogenic in humans, it will be a total breakthrough in HIV vaccines," says Hone, "because of the way it attacks the virus at its first contact."

[In recent HIV research, scientists have surmised that on mucosal membranes HIV may enter the body by attaching itself to cells called dendritic which act as watchdogs of the immune system. Typically, the dendritic cells capture invading microorganisms then set off an alarm for other immunity cells, such as T-cells which then fight off the invaders. But in the case of an HIV invasion, the virus can hitch a ride into the lymphoid tissues, where it proceeds to infect the T cells and others, thus tending to neutralize the immune system for its own benefit.]

The key to success of the IHV vaccines is that the carrier bacteria immediately infect the dendritic cells on mucous membranes in the digestive tract. The oral HIV DNA vaccine within the disarmed Salmonella, hitchhikes a ride to the mucosal cells, and then stimulates immunity by raising antibody responses throughout the mucosal lymphoid tissues and in the blood.

Previously, the IHV's vaccinating system was tested successfully for safety in human volunteers. The NIH grant will now support comprehensive testing of the best candidates vaccines through three inter-linked projects: 1. More preclinical animal trials of Salmonella-delivered vaccines which are in final building stages at IHV laboratories. 2. Tests to induce vaccine components that give newly enhanced antibody responses to HIV infection. And, 3. clinical trials in Baltimore.

Project one is directed by Hone who has over 15 years of experience in development and evaluation of Salmonella vectored vaccines. In previous studies, Hone developed a strain of Salmonella, which is now the central component of new oral vaccines against typhoid fever. He also led a study that was the first to document that a bacterial HIV-1 vaccine might work.

Hone and colleagues are building on what he calls "the gold standard" of HIV vaccine testing: the gp120 protein on the HIV coat. The virus puts gp120 in charge of directing entry into human cells. During the past few years, several trials at the National Institute of Allergy and Infectious Diseases have shown that using the gp120 is safe and well tolerated by human volunteers. The IHV researchers have genetically engineered two versions of the HIV gp120 protein for delivery in the Salmonella bacteria. Researchers have known about gp120 since 1987. But by itself delivery of gp120 DNA is not enough to raise sufficient antibodies to fight the invading HIV, says Hone who is confident that project two will solve the problem.

Project two is headed by Anthony L. Devico, associate professor, IHV, who has built structural variations of the molecular juncture, or joined complex of gp120 on HIV and a receptor point on human cells called CD4. Under normal circumstances, gp120 changes shape when it binds to CD4. The change exposes a special part of gp120 that allows, and is required for, easier entry into the human cell. In some HIV patients, researchers have detected strong antibodies against HIV that partially covered the special parts of gp120 on HIV thereby blocking entry into human cell.

Devico and the IHV team have formed a vaccination strategy to induce similar types of antibodies to bind to the special surfaces components of gp120.

Project three will be led by Lewis in collaboration with Edmund Tramont, M.D. Lewis has over 25 years of experience in immunology and Tramont has over 30 years experience in the conduct of vaccine trials.

Following a decade of steady progress, Hone says, "The key now is to get the trials finally underway. Of course, we know we will have new generations of these vaccines constantly coming on line. So, as this program proceeds, we will develop more and more sophisticated vaccine designs. In come cases, they will be tailored to each part of the epidemic around the world. Some of these candidate HIV vaccines will soon get into larger scale phase II and III clinical trials."


If the IAVI G001 HIV vaccine proves itself, why would it work? - Biology

Values & Goals gone screwy.
Commentary by
Jules Levin
Executive Director/Founder, NATAP
http://www.natap.org

HAART, HIV therapy, is clearly established and proven to save lives. Yet thousands of HIV patients cannot access HIV care and treatment through ADAP due to inadequate funding from Congress and the Adminstration. As well, Hepatitis C treatment with pegylated interferon plus ribavirin has been established as therapy that can save lives. Hepatitis appears to be the leading cause of death among people with HIV. Yet, most ADAPs do not provide this treatment for ADAP clients despite the fact that this therapy is the Standard of Care.

In these times we are so underfunded for ADAP that HIV+ individuals needing HIV therapy cannot access life-saving therapy for HIV and hepatitis. Each US state has an ADAP (AIDS Drug Assistance Program), which provides life-saving HIV and hepatitis treatment for patients who lack the finances to access treatment through private insurance or are unable to qualify for Medicaid. In order to provide adequate access to care and treatment for ADAP we need this $119 million but Congress and the Administration are offering $20 to $40 million. For several years ADAP has been severely underfunded and States are starting waiting lists and cutting patients off access to treatment through ADAP due to this underfunding. ADAP advocates have been asking for several hundred million dollars for several years to make ADAP whole but are repeatedly turned away. Is something screwy that we would spend $119 million on this vaccine study but not provide adequate funding to ADAP?

ADAPs are unable to provide Fuzeon, due to financial constraints, despite this new therapy being clearly established as a crucial drug needed for HIV treatment for patients with few or no treatment options remaining. Studies clearly establish Fuzeon as perhaps the only remaining therapy for many patients with drug resistance to the 3 main classes of HIV drugs: protease inhibitors, nucleosides, and NNRTIs. Patients with resistance to these classes of drugs are fully sensitive to Fuzeon, the first in a new class of drugs called entry inhibitors. Fuzeon is a fusion inhibitor, a type of entry inhibitor. This drug is expensive due to being difficult to manufacture, as it is the first in the new class of drugs.

It is clearly established that at the very least hepatitis is a leading cause of death in HIV. We invest millions of dollars in care and live-saving treatments for HIV, yet there is no firm commitment to provide equally needed care and treatment to address hepatitis C to patients co-infected with HIV and the hepatitis C virus. Not only do ADAPs not provide hepatitis C treatments for their clients but there is no commitment in Washington DC or in the States to address Hepatitis C. 30% of HIV-infected individuals have HCV, that is 300,000 HIV+ individuals. 60-90% of those infected with HIV by injection drug use, also have HCV. HIV therapy, HAART, does not slow or resolve HCV. Many HIV+ individuals with HIV well under control are dying of end stage liver disease due to hepatitis C.

In these times of competing political goals in the world of HIV, advocates and activists, government officials, and researchers all have competing demands related to AIDS vaccines, ADAP, HIV drug pricing, and more. What about the patients and their immediate needs?

Leading researchers and others clearly think that this $119 million expenditure on an AIDS vaccine trial is not productive. Perhaps the competing factions can consider that many individuals suffering with HIV and the leading cause of death in HIV, hepatitis, are not able to access care and treatment for therapies that are proven & established to save lives. Something appears screwy to me.

Experts: Thailand AIDS Vaccine Will Fail

By PAUL ELIAS
.c The Associated Press

SAN FRANCISCO (AP) - A $119 million federally funded experiment in which an AIDS vaccine is being tested on 16,000 volunteers in Thailand is doomed to fail and should never have been started, 22 leading HIV researchers charge.

The scientists allege the Thai volunteers are receiving a crude cocktail made of two antiquated AIDS vaccines, each of which failed previous human tests.

"They are taking two failed products and hoping that if they are combined that they are going to work," said Dennis Burton, an AIDS researcher at the Scripps Research Institute in La Jolla. "Everything I've seen about the Thai trial suggests that it doesn't have a prayer."

Burton and 21 other researchers - including Robert Gallo, co-discoverer of the AIDS virus - signed a short opinion piece published in Friday's issue of the journal Science.

The experiment is funded by the National Institutes of Health and the Pentagon and is being carried out by the Thai government.

U.S. government officials defended the research, saying it could yield a new weapon against a disease that has killed 28 million people and infected 42 million more, most of them in Africa.

But the 22 scientists complained the Thai experiment is diverting critical funding and energy from more promising vaccine candidates, including some of their own.

What's more, they said they fear public and political confidence in AIDS vaccine research will be hurt if the Thai experiment fails as they expect. It would be the third major flop of a large-scale AIDS vaccine experiment, and the second failure in Thailand.

Last year, AIDSVAX, a vaccine created by Brisbane, Calif.-based VaxGen Inc., failed to protect volunteers against the disease in a 5,400-person North American trial. The same vaccine failed in a 2,400-volunteer trial in Thailand in November.

Since then, VaxGen essentially has abandoned its pursuit of an AIDS vaccine.

Despite those failures, AIDSVAX is one of the vaccines being used in the current trial. It's the second part of a one-two punch called "prime boost" that its supporters see as the most promising approach to defeat the AIDS virus by provoking several different immune responses.

A VaxGen spokeswoman declined comment.

The prime piece of the Thai vaccine is ALVAC, created by Aventis Pasteur. An Aventis scientist defended the vaccine as worthy of continued development.

But the critics argue the NIH scrubbed a U.S.-based trial with the same two-vaccine cocktail two years ago because of failures in a smaller experiment.

That trial was canceled, in part, because the Thai test was starting, government officials said.

The U.S. trial targeted a different AIDS strain than the Thai test and was more narrowly focused. Still, the 22 scientists argue the two tests are similar enough to warrant cancellation of the Thai experiment.

Researchers already have inoculated about 500 volunteers since the experiment began in September and plan to give shots to 15,500 more people over the next two years. It will take about five years to see results.

U.S. government officials and advocacy groups contend the failed VaxGen vaccine has shown promise when used in combination with the Aventis vaccine in smaller experiments. More elaborate experiments are needed to prove whether the combination is effective, they say.

The National Institute of Allergy and Infectious Disease, the NIH branch managing the test, issued a sharp rebuttal Thursday, declaring "no evidentiary data is provided (by critics) to support the prediction and assertions."

Government officials said positive results from two earlier human tests gave them a scientific reason to proceed.

"That's why you need the trial," said Dr. John McNeil of the U.S. Army Medical Research and Material Command. "I get discouraged when nothing is done."

PUBLIC HEALTH:
Enhanced: A Sound Rationale Needed for Phase III HIV-1 Vaccine Trials

AUTHORS:
Dennis R. Burton,1 Ronald C. Desrosiers,2 Robert W. Doms,3 Mark B. Feinberg,4 Robert C. Gallo,5 Beatrice Hahn,6 James A. Hoxie,3 Eric Hunter,6 Bette Korber,7 Alan Landay,8 Michael M. Lederman,9 Judy Lieberman,2 Joseph M. McCune,10 John P. Moore,11 Neal Nathanson,3 Louis Picker,12 Douglas Richman,13 Charles Rinaldo,14 Mario Stevenson,15 David I. Watkins,16 Steven M. Wolinsky,17 Jerome A. Zack18[HN13]*

1The Scripps Research Institute, La Jolla, CA 2Harvard Medical School, Boston, MA 3University of Pennsylvania, Philadelphia, PA 4Emory University, Atlanta, GA 5Institute of Human Virology, Baltimore, MD 6University of Alabama at Birmingham 7Santa Fe Institute, Santa Fe, NM 8Rush Medical College, Chicago, IL 9Case-Western Reserve University, Cleveland, OH 10The Gladstone Institute for Virology and Immunology, San Francisco, CA 11Weill Medical College of Cornell University, New York, NY 12Oregon Health and Science University, Portland, OR 13University of California, San Diego, and San Diego Veterans Affairs Healthcare System 14University of Pittsburgh, Pittsburgh, PA 15University of Massachusetts Medical School, Worcester, MA 16University of Wisconsin, Madison, WI 17Northwestern University, Chicago, IL 18University of California, Los Angeles, CA, USA.

SUMMARY: Concerns are expressed by a group of AIDS researchers about the U.S. government's plans to conduct a phase III trial of a combination HIV-1 vaccine in Thailand despite the cancellation of a trial of a very similar combination vaccine in the U.S.A. last year. One of the vaccine components, recombinant monomeric gp120, has already been shown to be ineffective in phase III trials in Thailand and the United States the other component, a recombinant canarypox vector, is also poorly immunogenic. The scientific rationale that has been offered for the new trial in Thailand is considered by the authors to be weak.

The need for a human immunodeficiency virus-1 (HIV-1) vaccine [HN1] is unquestioned, and we strongly support its development as the highest AIDS research priority. We have a concern about the wisdom of the U.S. government's sponsoring a recently initiated phase III trial [HN2] in Thailand of a vaccine made from the live-replicating canarypox vector ALVAC (from Aventis Pasteur) [HN3] with a boost of monomeric gp120 (from VaxGen) [HN4] (1). The original aim of this trial was to determine whether a combination of immunogens designed to induce cellular immunity (ALVAC) and humoral immunity [HN5] (gp120) could prevent infection and/or lead to the immune control of HIV-1 replication postinfection. These remain questions fundamentally worth addressing, but we doubt whether these immunogens have any prospect of stimulating immune responses anywhere near adequate for these purposes.

A phase III trial of similar design was scheduled to be conducted in the U.S.A. by the HIV Vaccine Trials Network (HVTN) [HN6], the world's largest consortium of AIDS vaccine scientists and clinicians. However, the trial was canceled last year. [HN7] Multiple phase I and II clinical trials have revealed that the ALVAC vector is poorly immunogenic (2). The gp120 component has now been proven in phase III trials in the United States and Thailand to be completely incapable of preventing or ameliorating HIV-1 infection (1, 3). [HN8] There are no persuasive data to suggest that the combination of ALVAC and gp120 could induce better cellular [CD8+ cytotoxic T lymphocyte (CTL)] [HN9] or humoral (neutralizing antibody [HN10]) responses than either component can alone. Instead, the rationale for the Thai trial is reported to have now shifted toward an exploration of the hypothesis that the combination ALVAC + gp120 vaccine might induce an improved CD4+ T helper (TH) cell response [HN11] that would enhance host defenses (1). The evidence underlying this hypothesis is derived from phase I/II trials of the same or very similar vaccines and is, in our opinion, extremely weak (4-6). Moreover, the same data were available to the HVTN. We concur with the HVTN's decision not to proceed with a phase III trial of the ALVAC + gp120 vaccine (2). What scientific reasons mandate a different decision for the Thai trial? We also take issue with the scientific rationale for the revised hypothesis underlying the trial (1). Merely trying to answer a question about the protective role of the TH response does not seem to justify an experiment on this scale. Whether induction of TH responses by the gp120 component could enhance the breadth or magnitude of CTL responses to the ALVAC vector sufficiently could be answered rapidly by a small trial using methodology that was not available at the time of the earlier studies (4-6).

The cost of the phase III trial in Thailand is reported to be $119m, with at least $3m for the purchase of the gp120 component from its commercial manufacturer, itself a controversial point based on past precedent (7). The trial will involve 16,000 volunteers. [HN12] Approval was obtained from several committees, including one from the World Health Organization. But the latter committee's recommendation to proceed was made over a year before the results of the gp120 efficacy trial in Thailand were available, and it was made irrespective of the outcome of that trial (1). Our opinion is that the overall approval process lacked input from independent immunologists and virologists who could have judged whether the trial was scientifically meritorious. The U.S. National Institutes of Health (NIH) investment in basic and applied immunology research has been massive and appropriate over the past 15 years the cumulative expertise gained should be used when important strategic decisions are made.

Society expects the scientific community to develop a vaccine to counter the AIDS pandemic, but there are adverse consequences to conducting large-scale trials of inadequate HIV-1 vaccines. We have recently seen two large phase III trials of immunogens that, all too predictably, failed to generate protective immunity (1, 2). We seriously question whether it is sensible now to conduct a third trial that, in our opinion, is no more likely to generate a meaningful level of protection against infection or disease. One price for repetitive failure could be crucial erosion of confidence by the public and politicians in our capability of developing an effective AIDS vaccine collectively. This seems to us to be another readily predictable scenario that is best prevented.

Phase III trials are, ultimately, the only way to judge HIV-1 vaccine efficacy, but sometimes a formal end point is not needed. Applying judgment about the value of existing data is an essential part of the scientific process when determining whether or not to move ahead with any experiment. The failure of the gp120-only vaccine was, for example, fully predicted by phase II trial data (8). For a phase III trial to be justifiable, there should be a reasonable prospect that the vaccine will benefit the study population, i.e., that it will protect at least some of the participants from HIV-1 infection or its consequences. The decision about whether or not to proceed with mounting a phase III HIV-1 vaccine trial needs to take into account the likelihood of success and the consequences of failure, the value of what can realistically be learned, and the human and financial costs involved. As a whole, the scientific community must do a better job of bringing truly promising vaccine candidates to this stage of development and beyond. More highly immunogenic HIV-1 vaccines that offer a greater hope of success than the ALVAC-gp120 combination are, in fact, now in early-phase clinical trials.

1. J. Cohen, Science 302, 1309 (2003).
2. J. Cohen, Science 299, 1290 (2003).
3. J. Cohen, Science 295, 1616 (2002).
4. M. L. Clements-Mann et al., J. Infect. Dis. 177, 1230 (1998) [Medline].
5. G. J. Gorse et al., Vaccine 19, 1806 (2001) [Medline].
6. S. Ratto-Kim et al., J. Acquir. Immune Defic. Syndr. 32, 9 (2003) [Medline].
7. J. Cohen, Shots in the Dark: The Wayward Search for an AIDS Vaccine (Norton, New York, 2001) [publisher's information].
8. R. I. Connor et al., J. Virol. 72, 1552 (1998) [Medline] [Full text].

Numbered Hypernotes (HN)

1. HIV vaccines. Search for a vaccine is a presentation on NOVA Online's Surviving AIDS Web site. AIDSinfo offers a resource page and overview of vaccines. The World Health Organization's HIV/AIDS Web site offers an introduction to HIV vaccines. NIAID makes available a May 2003 fact sheet titled "Challenges in designing HIV vaccines" and a August 2003 fact sheet titled "Clinical research on HIV vaccines," as well as the online brochures Understanding Vaccines and HIV Vaccines Explained (in PDF format). The NIAID Division of AIDS offers a resource page on HIV vaccines. IAVI provides an overview titled "Preventive AIDS vaccine approaches currently in human testing" and the IAVI Database of Preventive AIDS Vaccines in Human Trials. The Pipeline Project, a collaboration of the UCSF Center for HIV Information and the HIV Vaccine Trials Network, provides information about vaccines in development links to Internet resources on vaccine development are included. HIVandHepatitis.com offers news reports about HIV vaccines. The Body, an AIDS and HIV information resource, provides links to articles about HIV vaccines. The AIDScience archive from Science Online makes available a March 2002 article by H. Köhler, S. Müller, and V. Veljkovic titled "No hope for an AIDS vaccine soon."

2. Phases of clinical trails. Definitions of the phases of clinical trials are provided by the CenterWatch glossary. IAVI provides an introduction to the phases of clinical trials. ClinicalTrials.gov provides an introduction to clinical trials. D. Stevens, Department of Pediatrics, University of South Dakota School of Medicine, provides lecture notes on clinical trials.

3. Canarypox vector ALVAC from Aventis Pasteur. Canarypox, vector, and ALVAC-HIV are defined in the HIV Vaccine Glossary. Aventis Pasteur provides an introduction to its R&D program. Aventis makes available a 8 July 2002 press release titled "Aventis Pasteur and AIDS vaccine research: An overview" the fact sheets on ALVAC and Prime Boost are also available in PDF format. The IAVI Database of Preventive AIDS Vaccines has an entry for ALVAC vCP1521 (the vector to be used in the phase III trial in Thailand).

4. VaxGen's gp120 vaccine. The NIAID HIV Vaccine Glossary defines gp120. VaxGen provides information about its AIDSVAX HIV vaccine candidates and the associated clinical trials. Information about gp120 vaccines is provided by aidsmap.com.

5. Cellular and humoral immunity. Humoral immunity and cell-mediated immunity are defined by the AIDSinfo glossary. Understanding the Immune System is a presentation of the News Center of the National Cancer Institute. S. Baron's Medical Microbiology includes an immunology overview. Kimball's Biology Pages offers an introduction to cell-mediated immunity. J. Decker offers tutorials on humoral immunity and cell-mediated immunity for an immunology course. P. Bugl provides introductions to cell-mediated immunity and humoral immunity in lecture notes for a course on epidemics and AIDS. HIV InSite provides information on humoral and cellular immune responses in the presentation on the science of HIV vaccine development.

6. The HIV Vaccine Trials Network, formed in 1999 by the NIAID Division of AIDS, conducts all phases of clinical trials, from evaluating candidate vaccines for safety and the ability to stimulate immune responses to testing vaccine efficacy.

7. Cancellation of the U.S. phase III trial. NIAID issued a 25 February 2002 press release titled "NIAID phase III HIV vaccine trial to determine correlates of protection will not proceed." The January-February 2002 issue of the IVAI Report had an article by P. Kahn titled "NIH drops plans for phase III trial." The 1 March 2002 issue of Science had a News of the Week article by J. Cohen titled "Disappointing data scuttle plans for large-scale AIDS vaccine trial."

8. Previous trials. The IAVI Database of Preventive AIDS Vaccines provides information on ALVAC vCP1452 and ALVAC vCP205 trials, as well as information on AIDSVAX B/E and AIDSVAX B/B trials. Information about ALVAC trials is provided by aidsmap.com. VaxGen issued a 24 February 2003 press release titled "VaxGen announces initial results of its phase III AIDS vaccine trial" and a 12 November 2003 press release titled "VaxGen announces results of its phase III HIV vaccine trial in Thailand: Vaccine fails to meet endpoints." The 28 February 2003 issue of Science had a News of the Week article by J. Cohen titled "AIDS vaccine trial produces disappointment and confusion." The 7 March 2003 issue had a News of the Week article by J. Cohen titled "Vaccine results lose significance under scrutiny." The 4 April 2003 issue had a News of the Week article by J. Cohen titled "A setback and an advance on the AIDS vaccine front." BioMed Central makes available a 7 November 2003 daily news story (provided by The Scientist) by R. Walgate titled "AIDS answers and questions: Failed vaccine trial in Thailand teaches many lessons, says the UN's José Esparza."

9. CD8+ cytotoxic T lymphocyte. CD8+ T lymphocyte and cytotoxic T lymphocyte (CTL) are defined by the HIV Vaccine Glossary. Dalhousie University School of Medicine's Immunology Book Case provides introductions to cytotoxic T cells and cytotoxic T lymphocyte activity. Kimball's Biology Pages offers an introduction to cytotoxic T lymphocytes.

10. Neutralizing antibody is defined in the HIV vaccine glossary. IAVI issued a 9 July 2002 press release titled "IAVI launches Neutralizing Antibody Consortium to accelerate search for preventive AIDS vaccine."

11. CD4+ T helper cells. CD4+ T lymphocyte is defined by the HIV Vaccine glossary. CD4+ cells are defined in the AIDSinfo glossary. An entry for helper T cell is included in the Wikipedia online encyclopedia. Kimball's Biology Pages offers an introduction to CD4+ T cells and T helper cells.

12. The phase III trial in Thailand. UNAIDS provides a brief on Thailand's response to AIDS. The HIV/AIDS Surveillance Web site of the U.S. Census Bureau makes available in PDF format an HIV/AIDS profile of Thailand. The Thai Prime-Boost HIV Vaccine Phase III Trial Web site provides a FAQ and information about the researchers. The AIDS Vaccine Clearinghouse provides information about the Thailand trial. The IAVI Database of Preventive AIDS Vaccines provides information on the Thailand phase III trial. IVAI provides a 28 February 2002 news report titled "U.S. government announces plans for final stage human trial of ALVAC-AIDSVAX in Thailand." The October-December 2001 issue of the IAVI Report (a special issue on Thailand & AIDS Vaccines) had an article by P. Kahn titled "Thailand prepares for a new phase III trial" and an article titled "Thailand, AIDS and vaccines: An interview with Supachai Rerks Ngarm." The 21 November 2003 issue of Science had a News of the Week article by J. Cohen titled "AIDS vaccine still alive as booster after second failure in Thailand."

13. Dennis R. Burton is at the Scripps Research Institute. Ronald C. Desrosiers and Judy Lieberman are at Harvard Medical School. Robert W. Doms, James A. Hoxie, and Neal Nathanson are at the University of Pennsylvania. Mark B. Feinberg is at Emory University Robert C. Gallo is at the Institute of Human Virology. Beatrice Hahn and Eric Hunter are at the University of Alabama at Birmingham. Bette Korber is at the Santa Fe Institute. Alan Landay is at the Rush Medical College. Michael M. Lederman is at Case Western Reserve University. Joseph M. McCune is at the Gladstone Institute for Virology and Immunology. John P. Moore is at the Weill Medical College of Cornell University. Louis Picker is at the Oregon Health and Science University. Douglas Richman is at the University of California, San Diego, and San Diego Veterans Affairs Healthcare System. Charles Rinaldo is at the University of Pittsburgh. Mario Stevenson is at the University of Massachusetts Medical School. David I. Watkins is at the University of Wisconsin. Steven M. Wolinsky is at Northwestern University. Jerome A. Zack is at the University of California, Los Angeles.


Background

Since it was first reported in 1981, the disease has been misrepresented in mass-media as gay scourge, drug-user's Black Death, a punishment on sinful, etc. The list of stigma goes on mainly due to the unique biology of the causative agent which spreads both venereally and by contaminated blood products. The disease is caused by a retrovirus of the Lentivirus genus under the name of Human Immunodeficiency Virus (HIV-1). Once in the human body, the virus replicates mainly in CD4 + lymphocytes and leads to a progressive degenerative immune deficiency disease, known as acquired immunodeficiency syndrome (AIDS). In just over two decades the virus has killed more than 20 million humans and infected over 42 million people globally with the latest yearly infection rate of over 6 million [1]. Considering the magnitude of the HIV/AIDS epidemic, the efforts in fighting the disease have been extraordinary through developing therapies and potential vaccines. The literature is full with publications and reviews on the subject. Even a deadline has been suggested by President Clinton in 1997 to develop a vaccine by 2007.

In its 2004 report, the AIDS Vaccine Advocacy Coalition (AVAC) documented that there will not be a safe and effective vaccine in 2007 and that we need to "focus on the long haul and set an agenda for sustained and sustainable action that stretches well beyond 2007" [2]. The problem is further compounded by the emergence of drug-resistant variant strains that makes one ask the question: is the replication machinery of HIV so unique that it can easily find a way to evade the therapeutic and preventive approaches, thus, making it difficult to develop a preventive measure against HIV/AIDS? In the following sections I am looking into the unique biology of HIV infection as an impediment to the preventive efforts against HIV/AIDS and also into the possible strategies to overcome such obstacle for developing a vaccine. This article is not intended to be an exhaustive review of research articles on HIV vaccine development. It summarizes the difficult aspects of HIV vaccine development and discusses prospects of novel vaccination strategies.

Uniqueness of HIV-1 infection

With a genome of approximately nine thousand nucleotides, HIV-1 has packaged the necessary information in overlapping open reading frames to encode 15 proteins from multiply-spliced mRNAs (Figure 1) that provide the unique characteristics to its infection. HIV establishes infection (especially in CD4+ T lymphocytes) by integrating its genome into the host cell genome. The virus spreads by either venereal contact, direct injection of contaminated blood products in the hematogenous circulation or from mother to child during pregnancy or birth. Therefore, any vaccine to be effective must induce mucosal immunity to prevent venereal spread, and the systemic immunity to control the other modes of transmission. A successful vaccine would also be expected to stimulate innate immune system, generate high titers of neutralizing antibodies and strong cellular immune responses leading to persistent and broad spectrum immunity to cover all subtypes of HIV. The initial burst of virus replication following the exposure appears to be contained by a partial antiviral immune response, which is not yet fully characterized. Despite this initial immune response, HIV continues to replicate persistently in infected individuals. The persistent replication in the presence of an immune response and integration of its genetic material in the host genome are the most troubling aspects of HIV-1 biology for developing a vaccine.

Genome organization of HIV-1. The open reading frames for various polypeptides are shown as rectangles and the transcription initiation site as an arrow. Multiply-spliced mRNA transcripts encoding various proteins are shown with splice-sites together with 5'-cap and 3' polyA tails. Major translated polypeptides from these mRNAs are finally processed to produce 15 protein molecules.

Additionally, the replication machinery of the virus is so inaccurate that it generates new mutants for virtually every virion produced in an infected individual, thus, creating a myriad of new and unique viral particles every day [3]. A high number of recombination events occurring during the replication further compounds the genetic heterogeneity. It is this genetic diversity that also accounts for the distinct subtypes or clades of HIV occurring in geographically distinct regions of the globe: for example, clade B viruses cause AIDS epidemic predominantly in the Western Hemisphere, clade C viruses in the sub-Saharan Africa and clade B, C and E in Asian countries. The extraordinary genetic variations create a heterogeneous virus population, often termed as "swarm" or "quasi-species" in an infected individual, which continually supplies new antigenic variants against which no immune response has yet been developed. The mutant viruses keep continually damaging or killing the cells of the immune system (mainly CD4 + lymphocytes) and, thus progressively destroy the body's ability to fight opportunistic infections and certain cancers resulting in AIDS and finally death in 7 to 10 years.

The evolution of HIV is also believed to be the result of genetic heterogeneity. A large number of lentiviruses exist in African nonhuman primates as apathogenic species-restricted simian immunodeficiency viruses (SIV) [4]. Wild populations of chimpanzees are infected with HIV-like viruses which appear to have evolved through recombination of distinct SIV isolates [5] and have zoonotically infected humans to cause the AIDS epidemic [6]. SIV from African monkeys also cause AIDS-like disease in Asian macaques, which are used as nonhuman primate models for understanding viral pathogenesis and evaluating vaccine strategies against HIV [7].

As mentioned above, a potent defense against HIV would require both arms of the immune system: humoral and cellular immunity. The protective role of HIV-neutralizing antibodies in natural infection seems to be insufficient since such antibodies are detected only after several weeks of initial containment of virus replication. Moreover, only low titers of neutralizing antibody are detected in HIV-1 infected individuals. Cellular immune responses seem to have a dominant role in HIV-1 containment as evidenced by several in vivo and in vitro observations: the emergence of HIV-specific CD8 + CTL responses coincides with the initial containment of viral replication in acute infections [8] high levels of HIV-specific CTL in the peripheral blood of infected individuals are predictive of good clinical status, measured by plasma viral RNA loads [9] in vitro replication of HIV-1 in CD4 + lymphocytes can be inhibited by CD8 + lymphocytes possibly through direct cytotoxicity and other soluble factors including beta chemokines [10, 11]. The most compelling evidence of the importance of CD8 + lymphocytes in controlling HIV replication came from animal models. Monkeys depleted of CD8 + lymphocytes by administering anti-CD8 monoclonal antibodies were unable to control viral replication upon infection with SIV. These animals died of AIDS-like disease with an accelerated course [12].

Mutations have been shown to help HIV escape recognition by CTL [13]. Escape variants happen to be the cause of an abrupt increase in viral replication and decreased immune function in infected individuals. The daunting challenge is to devise an immunogen that can induce high-frequency CTL and antibody responses, which are capable of neutralizing a variety of HIV isolates.

Failure of traditional preventive approaches

Traditional strategies for vaccination such as attenuated- or inactivated-viruses, passive immunization and purified or recombinant proteins (Figure 2) safely protect humans against a variety of viral pathogens such as smallpox, measles, polio, rabies, hepatitis B virus, etc. These approaches are not proving useful against HIV-1 due to the unique biology of the infection and failure in eliciting potent immune responses. A detailed overview of various vaccine approaches has been compiled elsewhere [14].

Some of the vaccine strategies against HIV currently under investigation are shown. The HIV virion with RNA and envelope (Env) glycoproteins gp41 and gp120 is also shown.

In SIV-macaque models, gene-deleted SIV known to be pathogenically attenuated were found to cause disease in monkeys [15] and the degree of protection was found to be inversely related to the level of attenuation [16]. Similarly, humans who received blood products infected with an HIV-1 isolate harboring a large genetic deletion appeared initially to be free of disease but later developed AIDS [17]. The animal models show that an attenuated virus confers protection only if it can replicate at low but consistent levels. However, even the low level of replication over prolonged periods might afford the virus time to mutate and revert to pathogenic variants. The safety concerns over this modality killed the enthusiasm among investigators for pursuing it as a vaccine approach. Furthermore, chemically inactivated virus vaccines have induced effective immunity in monkeys against SIV [18]. However, this approach is very restricted in duration and spectrum of immune response and fails to induce immunity against genetically diverse viral isolates. Inactivated vaccines also fail to generate CTL responses, thus, there is little optimism that this approach will prove to be useful. Nevertheless, non-infectious particle immunization strategies are being pursued with the expectation that these virus-like particles can be easily manipulated and are safer than inactivated virus. Passive immunization studies, mainly conducted in animal models, have not been encouraging. Trkola et al. [19] evaluated the efficacy of passively transferred neutralizing monoclonal antibodies (2G12, 2F5 and 4E10) in suppressing viral rebound in individuals undergoing interruption of antiretroviral therapy. Such an approach would help prolong the life of infected individuals but mass production of high-titer monoclonal antibodies against variant strains may not be a cost effective approach. Finally, highly purified viral proteins expressed in mammalian or bacterial cells using recombinant DNA technologies fail to induce CTL responses or any immunity against genetically diverse HIV isolates. Efficacy trials of such vaccines conducted in United States and Thailand showed no protection against HIV-1 [20]. The failure of traditional approaches asks for exploring novel vaccine strategies against this virus. However, neutralizing monoclonal antibodies against HIV hold some promise and their importance is discussed in the following chapter.

Prospects of novel vaccination strategies

Live recombinant viral and bacterial vectors and plasmid DNA have been explored as novel approaches for delivering HIV proteins as immunogens (Figure 2). Results of several exciting studies in animal models employing these novel approaches have been reviewed elsewhere [14]. The plasmid DNA is known to be less immunogenic, particularly in inducing CTL, in clinical testing in humans than in animal models. Several improvements such as codon-optimization for expression of viral proteins in mammalian cells, alteration in regulatory elements, inclusion of cytokine expressing genes and novel formulations with polymers are being pursued to increase immunogenicity of DNA vaccines.

Genes of HIV and SIV have also been expressed in microorganisms that have a proven record of being safe and effective live-attenuated vaccines. A long list of such live recombinant vectors includes attenuated vaccinia and other pox-, alpha-, adeno- and measles viruses, attenuated mycobacterium Bacille Calmette-Guerin, Salmonella, Shigella and others. Since several of such vectors are replication competent, expression of HIV proteins from them is expected to induce CTL. Many of the vaccine studies combine various approaches in a prime-boost fashion for avoiding immune responses to the vectors. Results of several animal studies using these modalities have been encouraging, but observations in early phase clinical trials in humans have not been promising. Some of the trials were stopped at various stages owing to adverse reactions to the delivering vector or the inability of the expressed immunogen to cover genetically diverse isolates prevalent in the geographical areas. Nevertheless, the outcome of several ongoing clinical trials is expected to deliver the good news about safe vaccine delivery vectors and, if possible, an effective vaccine against a particular strain of HIV-1 [21].

In anther approach, in vitro antigen-pulsed dendritic cells (DC) upon re-injection show improvement in cellular immune responses against the same HIV-1 strain [22]. This approach has potential as a therapeutic vaccine for already ongoing HIV infections but is again limited in not inducing immunity against genetically diverse isolates. DC primed with a cocktail of peptides carrying diverse immunogenic epitopes is an exciting avenue of investigation for inducing immunity against heterogeneous strains of HIV-1. Although ex vivo loading of DC seems an exciting avenue for individualized therapeutic intervention, the financial cost of such an approach makes it unattractive endeavor for a prophylactic vaccine in developing countries.

Lately, several neutralizing monoclonal antibodies have been reported [23]. The neutralizing antibodies have potential only if they are able to prevent the binding of cell-free HIV virions to the receptor (CD4) and/or co-receptor (CXCR4/CCR5) on the host cells, thus inhibiting the entry of the virus. Two monoclonal antibodies (2F5 and 4E10) have been very recently demonstrated to bind to membrane proximal linear epitopes of gp41 and broadly neutralize HIV across clades [24]. The crystal structure of the epitope-binding site of 4E10 has already been determined [25]. This information is expected to help design right immunogens that would induce 4E10-like neutralizing antibodies and potentially prevent entry of the virus in the host cells, thus halting further replication and transmission of HIV-1.

A vaccine for beating the genetic heterogeneity and antigenic diversity

The accumulated experience in vaccine development against HIV highlights the challenge in devising an immunogen that can mount a potent immune response against the continuously arising viral variants and the AIDS epidemic. Using geographically prevalent strains or consensus sequences have so far been the strategies for developing vaccines against antigenic variants of HIV-1 [26]. Lately, clinical trials have also been initiated using combinations of HIV-1 candidate vaccines with the idea of combining the antigenic strength of each vaccine against different clades [27]. The outcome of such combo vaccines remains yet to be seen.

Easier said than done, one can think of utilizing the error-prone replication machinery of HIV to generate potential immunogens that would represent all the variants. In this strategy, one would first replace the transcription-transactivator Tat/TAR axis of HIV with controllable transcription regulators and take out other non-structural protein genes such as nef in order to weaken the virus. Several investigators have been pursuing the tetracycline/doxycycline-controlled transcriptional regulator (tetO/tTA or tetO/rtTA) systems [28, 29]. This system could be used to generate immunogens in vitro or in vivo. Since the system has also been shown to have background expression [28], its in vivo utilization would require enhanced transcriptional control. More stringency could be added to the system by combining it with the tetO silencer (tTS) that would abrogate the background expression or leakiness [30]. The HIV genome also has a size constraint for inserting additional sequences. To circumvent this hurdle, multiple genomes of HIV can be combined in parallel using the drug-controlled transcription-transactivation system, thus compensating for the insert size constraints and bringing the system under stringent control. This way one would expect to switch on or off the HIV replication machinery in a controlled fashion and generate the necessary immunogens for covering the genetic heterogeneity by utilizing the error-prone HIV replication machinery itself. This approach would need thorough investigation first in vitro and later in animals using SIV as a model. The major concerns over this approach would be recombination between the multiple genomes of HIV resulting in pathogenic variants. Moreover, if such viruses capture the cellular promoter/enhancer elements, the conditional replication control would be lost resulting in a pathogenic virus.

Alternatively, one can utilize the knowledge of human genome and HIV sequences for creating "swarm or quasi-species" in compu by digitally generating sequences of HIV through combining all the possible substitutions at each nucleotide position. The putative immunogens from such sequence combinations would be identified by digitally matching them to the three-dimensional structures of the human MHC molecules (HLA) for the feasibility of CTL epitopes presentable to the immune system. These epitopes would be screened for their relevance to generate CTL in vitro against the prevalent HIV strains. A cocktail of such epitopes would be delivered using live-vectors or primed-DC for generating protective immune responses against the genetic variants. Similarly, putative neutralizing antibody inducing epitopes can also be generated utilizing the information on antigen-binding sites of neutralizing antibodies. These designer cocktails can be readjusted through the digital data-base of prevalent variant viral sequences. Studies on representative or "immunogenic consensus sequence" epitopes from multiple viral variants using computer-driven methods are already underway [31]. The major difficulty in this approach could be the enormity of the size of the digital data-base and servers needed to generate and analyze such epitopes in compu, and the optimal delivery vehicles needed for the cocktails. With the latest pledge from Microsoft ® for helping investigators to devise strategies against HIV [32], the necessary expertise and digital data-base size appear not to be the limiting factors. The expected positive outcomes of various vaccine approaches currently underway make me believe that an optimal delivery vehicle would soon be available. Given the right tools to combat the strength of HIV in generating diversity, a safe and effective vaccine against HIV/AIDS can be devised in the near future.


Materials and methods

Key resources table

Reagent type
(species) or resource
DesignationSource or referenceIdentifiersAdditional information
Chemical compound, drugPropidium iodideLife TechnologiesCat# P1304MP
AntibodyAnti-CD3 (FITC, clone UCHT1)BiolegendCat# 300406, RRID:AB_31406010 μg/ml
AntibodyAnti-CD14 (FITC, clone HCD14)BiolegendCat# 325604, RRID:AB_830677Dilution (1:100)
AntibodyAnti-IgM (FITC, clone MHM-88)BiolegendCat# 314506, RRID:AB_493009Dilution (1:100)
AntibodyAnti-CD20 (PE-cy7, clone 2H7)BD BiosciencesCat# 560735, RRID:AB_1727450Dilution (1:100)
AntibodyAnti-CD19 (BV421, clone HIB19)BiolegendCat# 302233, RRID:AB_10897802Dilution (1:100)
AntibodyAnti-IgA (FITC, clone IS11-8E10)Miltenyi BiotecCat# 130-093-071, RRID:AB_1036156Dilution (1:100)
AntibodyhCD40L His tagBPS BiosciencesCat# 71191Dilution (1:100)
Chemical compound, drugStreptavidin conjugated to PE or AlexaFluor 647Life Technologies
Recombinant proteinClade B JR-CSF gp120, JR-FL gp140, 92BR020 gp120, clade A BG505 SOSIP, clade C IAVI C22 gp120Duke Human Vaccine Institute, protein production facility
Cell line
(Homo sapiens)
TZM-bl cellsNIH AIDS
Reagent Program
Cat# 8129�, RRID:CVCL_B478
Recombinant DNA reagentAC10.0.29, RHPA4259.7, THRO4156.18, REJO4541.67, WITO4160.33, TRO.11, SC422661.8, QH0692.42, CAAN5342.A2, PVO.4 TRJO4551.58Seaman lab Plasmids
Commercial assay or kitAmpure XP beadsBeckman CoulterCat# A63881
Commercial assay or kitQuant-iT PicoGreen dsDNA Assay KitInvitrogenCat# P7589
Software, algorithmFlowJohttps://www.flowjo.com/solutions/flowjoRRID:SCR_008520
Software, algorithmIgBLASThttps://www.ncbi.nlm.nih.gov/igblast/RRID:SCR_002873
Software, algorithm454 GS FLX data analysis softwareRocheRRID:SCR_018028
Software, algorithmR version 4.0.0https://cloud.r-project.orgRRID:SCR_001905
Software, algorithmIgphyml (version 1.1.0)https://igphyml.readthedocs.io/en/latest/
Software, algorithmAlakazam (version 1.0.0)https://alakazam.readthedocs.io/en/1.0.1/news/

Human subjects

A total of 22 HIV-infected individuals were recruited for this study. All participants underwent leukapheresis and routine blood draws as per study protocol. All subjects signed informed consent, and the study was approved by the MGH/Partners Institutional Review Board (Protocol # 2003P001894).

Neutralization assay

HIV-1 neutralization breadth was assessed using the Tzm-bl cell-based pseudovirus neutralization assay, as described (Sarzotti-Kelsoe et al., 2014), against a standard panel of Env-pseudoviruses derived from nine clade B tier 2 viruses: AC10.0.29, RHPA4259.7, THRO4156.18, REJO4541.67, WITO4160.33, TRO.11, SC422661.8, QH0692.42, CAAN5342.A2, and two tier 3 viruses: PVO.4 and TRJO4551.58 (Li et al., 2005). Murine leukemia virus (MuLV) was included in all assays as a negative control. Neutralization titers (50% inhibitory dose [ID50]) were defined as the reciprocal of the plasma sample dilution that caused a 50% reduction in relative luminescence units (RLUs) compared to virus control wells after subtraction of background RLUs. Neutralization breadth was determined as the proportion of pseudoviruses with an ID50 score threefold above background titers observed against MuLV negative control virus (3× ID50 of MuLV) (Sarzotti-Kelsoe et al., 2014).

Cell lines

TZM-bl cells (also called JC53BL-13) were obtained from the NIH AIDS Reagent Program and authenticated by (1) morphology and growth characteristics, (2) cell surface expression of CD4 and co-receptors was assessed by flow cytometry, and (3) susceptibility in vitro to HIV, with readout being firefly Luc activity in infected cell lysates. All cell lines were tested to confirm absence of mycoplasma contamination.

Single-cell flow cytometry sorting

Isolated cells were stained with fluorochrome-antibody conjugates and reagents to identify antigen-specific MBCs. The panel consisted of propidium iodide (Life Technologies) CD3 (FITC, clone UCHT1), CD14 (FITC, clone HCD14), IgM (FITC, clone MHM-88), CD20 (PE-cy7, clone 2H7), CD19 (BV421, clone HIB19) (All Biolegend) IgA (FITC, clone IS11-8E10) (Miltenyi Biotec). Preformed conjugates for antigen-specific B-cell sorting were made as described (Sok et al., 2014) using streptavidin conjugated to PE or AlexaFluor 647 (Life Technologies). B-cell probes were made using clade B JR-CSF gp120, JR-FL gp140, 92BR020 gp120, clade A BG505 SOSIP, and clade C IAVI C22 gp120 tags (Duke Human Vaccine Institute, protein production facility) and a cocktail of all antigens was used for cell sorting. IgG+ B-cells were defined as CD3/14−, CD19+, CD20+, and IgA/IgM- antigen-specific B-cells positive for probes in either PE or APC color were sorted into 96-well U-bottom plates containing 200 µl of B-cell culture medium (IMDM supplemented with FBS, Normocin, hIL-2, hIL-21, hCD40L His tag, and anti-His antibody). After 4-day culture, the B-cells were sorted into microtiter plates at one cell per well. Sorted plates were frozen immediately and maintained at �ଌ before reverse transcription (RT)/PCR.

BCR sequencing

Natively paired variable region sequences from individual cells were generated by RT, cDNA barcoding, amplification, and sequencing as described previously (Tan et al., 2014 DeFalco et al., 2018). cDNA sequences were determined by 454 Titanium sequencing. A minimum of 10 reads for each chain (heavy and light) was required, and a contig was kept only if it included at least 90% of the reads for that chain from that well. V(D)J assignment and mutation identification was performed using IMGT reference sequences and IgBLAST through Immcantation analysis framework (Supplementary file 2). Percentage SHM was calculated by calling observed mutations of the entire input sequence compared to the germline sequence.

Analysis

Statistical analyses and visualizations were performed in R version 4.0.0 (Aprilꀤ,�). Subclass distribution, gene family, and gene usage analysis: to exclude potential bias caused by the number of input cells or sequences, we divided the number of occurrences of each repertoire signature by the total number of all sequences for each individual. Gene recombination profiles: to avoid skewing of mean frequencies when averaged across all individuals by individuals with high or low number of available sequences (in particular for sequences with higher than 15% heavy chain mutations), normalized frequencies were multiplied by a factor (number of unique clones per individual). For IGHV-IGLV recombinations, the highly mutated sequences were defined using only heavy chain mutation cutoff. CDRH3 length distributions consist of CDRH3 length of each unique clone. Kolmogorov-Smirnov test was used to compare the distributions between TN and NN repertoires.

Mean number of mutations between TN and NN were compared using unpaired two-samples t-test. All correlations were performed using Spearman’s correlation. Visualizations were performed using R package ggplot2 (version 3.3.0). The flow graph of IGHV/IGHJ/IGLV/IGLJ combinations were plotted using ggalluvial extension of ggplot2. Circos plots were generated using R package circlize (version 0.4.9) chordDiagram function. The layout for clonal network visualization was arranged using R package packcircles (version 0.3.3).

Clones were defined using DefineClones tool of the Immcantation analysis framework (50). Clones consist of sequences that meet the following criteria: (1) come from the same individual (2) share the same IGHV and IGHJ gene segment annotations (3) have equal CDRH3 length and (4) share sequence similarity calculated by nucleotide Hamming distance threshold of 0.16. Clonal groups were then split that have differing IGLV and IGLJ gene segment annotations.

The clonality measure was estimated using Gini index and calculated using R package bcRep (version 1.3.6) clones.giniIndex function.

Lineage trees were constructed using IgPhyML (version 1.1.0) (Stern et al., 2014). The HLP19 model was used to estimate maximum likelihood tree topologies. Clonal selection was estimated using ω, also called dN/dS, or the ratio of nonsynonymous (amino acid replacement) and synonymous (silent) mutation rates. A value of ω𢒁 indicates totally neutral amino acid evolution, ωρ negative selection, and ωϡ diversifying selection. The topology analyses were carried out using Alakazam (version 1.0.0) (Gupta et al., 2015) and the lineage trees were visualized using R ggtree (version 2.2.1).


Author information

Affiliations

Africa Health Research Institute, Durban, South Africa

HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa

Max Planck Institute for Infection Biology, Berlin, Germany

HIV Frontiers, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation, Seattle, WA, USA

Department of Medicine, University of California San Francisco, San Francisco, CA, USA

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Contributions

T.N. and S.G.D. produced the first draft. J.M.M. provided substantial additions and edits. All three edited and approved the final version.

Corresponding author


Herpesvirus

Herpesvirus vectors have been used most extensively in gene therapy applications related to the central or peripheral nervous system. The large enveloped double-stranded DNA viruses not only infect a variety of tissue types but also target mucosal surfaces and therefore are advantageous for elicitation of mucosal immune responses. The vectors can accommodate large foreign gene inserts and are biased for induction of Th1 cellular responses. Additionally, HSV-1 activates TLR2 for induction of pro-inflammatory cytokines and TLR9 for induction of type I interferons [ 38• ]. Both replication-competent and incompetent vectors have been developed [ 39 , 40 ]. While replication-competent herpesvirus vectors are advantageous in many applications for their persistence, replication-deficient hervesvirus vaccine vectors also induce durable immune responses [ 38• ]. Both vector types were previously evaluated in a SIV rhesus macaque model for protective efficacy [ 41 ]. Following immunization with the vectors that expressed the SIV env and nef genes, weak but persistent anti-SIV envelope antibodies were elicited, along with relatively weak and sporadic cellular immune responses. Nevertheless, following intrarectal challenge with pathogenic SIVmac239, two of seven immunized macaques were strongly protected and a third showed diminished chronic viremia, providing a basis for continued development of the herpesvirus vector system.

Using an improved replication-defective herpesvirus vector, engineered for prolonged expression of the transgene and prevention of MHC downregulation and blockade of the TAP peptide transporter [ 42 ], HSV recombinants encoding SIV env, gag, and rev-tat-nef genes were evaluated in rhesus macaques with and without prior priming with DNA vaccines expressing SIV Gag, Env, and Pol-Tat-Nef-Vif fusion proteins [ 43 ]. In contrast to the earlier study, strong cellular responses to Env and Gag were elicited together with anti-SIV antibodies readily detectable by ELISA, and possessing low-titer neutralizing activity against the neutralization-sensitive SIVmac251 strain. Following challenge with SIVmac239, modestly reduced acute phase viremia was observed in comparison to historical control animals, but the protection did not extend into the chronic phase of infection. Whether this vector will prove to be more effective in combination with cytokine adjuvants, other vectors, or booster immunizations with envelope protein will await future studies.


IAVI Announces Clinical Trial of Next-Generation HIV Vaccine Candidate Designed to Induce Antibodies to Block HIV Infection

NEW YORK — OCTOBER 9, 2018 — The International AIDS Vaccine Initiative (IAVI) announces the start of a Phase I clinical trial (IAVI G001) to test a novel vaccine candidate designed to stimulate the immune system to initiate a key first step in the generation of potent proteins, known as broadly neutralizing antibodies (bNAbs), against HIV. The trial will evaluate the safety of the candidate and the immune responses it is able to induce. The candidate, known as eOD-GT8 60mer, represents an important step forward in the quest to develop an HIV vaccine.

Computer image of the eOD-GT8 immune-stimulating protein. Image courtesy of Joseph Jardine, Sergey Menis, and William Schief of Scripps Research and IAVI.

Researchers widely agree that a vaccine that induces bNAbs will likely be the best way to confer durable protection against the virus. bNAbs are desirable because in laboratory experiments, they are effective against many of the genetically diverse strains of HIV, and in animal studies, they can block infection of a virus similar to HIV.

“The world urgently needs new ways to prevent HIV infection, and chief among these is a vaccine,” said Mark Feinberg, M.D., Ph.D., president and CEO of IAVI. “Fortunately, a new generation of HIV immunogen candidates, including eOD-GT8 60mer, is entering clinical trials. These candidates are being developed using highly sophisticated and elegant vaccine science and provide a precedent for vaccine strategies targeting the induction of specific immune responses believed to be critical in protecting against HIV infection.”

Over the past 15 years, scientists have gained an unprecedented understanding of the structure of HIV’s outermost envelope protein, which is the target of all bNAbs. From large cohort studies of HIV-infected volunteers, researchers isolated and characterized many bNAbs that develop naturally, but only rarely, during the course of HIV infection, and identified where they bind to the virus. These sites of vulnerability on the virus were then used to design vaccine immunogens, using what is referred to as a structure-based vaccine design approach. The eOD-GT8 60mer candidate is based on one of these sites targeted by bNAbs.

The candidate was developed in the laboratory of Dr. William Schief, director of vaccine design for IAVI’s Neutralizing Antibody Center (NAC) at Scripps Research and professor at Scripps. It is the first candidate to enter clinical trials that was designed using a structure-based vaccine approach, and it is the first in a sequence of engineered vaccine candidates that Dr. Schief and his colleagues are developing.

“In this trial, our goal is to prove that it is possible to induce responses from special, targeted B cells,” said Dr. Schief. “We’ll have a promising outcome if some of the vaccine recipients produce B cells expressing a specific type of antibody, whereas placebo recipients do not. This would confirm that we are able to induce the desired initial immune response, and the next step will be making technical refinements to improve performance.”

There are several steps involved in the development of bNAbs, and in animal studies, the eOD vaccine candidate successfully elicited antibodies that are precursors to the much more specialized antibodies that scientists classify as broadly neutralizing. It is envisioned that eOD or a similar engineered vaccine candidate would be the first in a series of vaccinations that would elicit the bNAbs believed to be needed to protect against HIV infection.

“This is a big moment, not just for HIV vaccines, but for vaccine science as a whole,” said Dr. Dennis Burton, scientific director of the NAC and chair of the Scripps Research Department of Immunology and Microbiology. “This trial is going to tell us how much control we can have over the immune responses induced by a targeted vaccine candidate. If this type of vaccine engineering is successful, it can be applied more broadly, bringing about a new day in vaccinology. If we can really drive immune responses in predictable ways, we can make better, more effective vaccines, not just for HIV but for other viruses, too.”

The IAVI G001 trial will enroll 48 healthy adult volunteers who will receive two doses of eOD-GT8 60mer, along with the AS01B 1 adjuvant developed by the pharmaceutical company GSK, or placebo. Adjuvants are substances used to enhance immune responses induced by a vaccine, and the AS01 adjuvant is used in licensed vaccines. The doses are spaced two months apart and are administered through intramuscular injection.

The trial is taking place at two sites: George Washington University (GW) in Washington, D.C., and the Fred Hutchinson Cancer Research Center in Seattle, Washington. At GW, the trial is led by Dr. David Diemert, associate professor in the Department of Medicine, who will serve as the principal investigator at this site, and Dr. Jeffrey Bethony, professor in the Department of Microbiology, Immunology, and Tropical Medicine, who will direct the specimen processing and biorepository aspects of the trial at GW. At the Fred Hutchinson Cancer Research Center, the trial is led by Dr. Julie McElrath, senior vice president and director of the Vaccine and Infectious Disease Division.

The Collaboration for AIDS Vaccine Discovery (CAVD) Comprehensive T-Cell Vaccine Immune Monitoring Consortium/The Dale and Betty Bumpers Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH), the CAVD Comprehensive Antibody Vaccine Immune Monitoring Consortium, and the Fred Hutchinson Cancer Research Center will be performing key analytical assays in support of the trial, to assess whether the targeted immune response is elicited. The CAVD Vaccine Immunology Statistical Center played a major role in the study design and analytical methods to evaluate the data.

Results of the IAVI G001 trial are expected in late 2019.

IAVI developed the eOD-GT8 60mer candidate with support from the Bill & Melinda Gates Foundation, the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at NIAID at the NIH, and Scripps Research.

Research at the NAC that contributed to the development of eOD-GT8 60mer was also made possible by the Dutch people through the Dutch Ministry of Foreign Trade & Development Cooperation and through the generous support of the American people through the United States Agency for International Development (USAID). USAID administers the U.S. foreign assistance program providing economic and humanitarian assistance in more than 120 countries worldwide. The contents are the responsibility of IAVI and do not necessarily reflect the views of USAID or the United States government.

About the IAVI Neutralizing Antibody Center at Scripps Research
The IAVI Neutralizing Antibody Center (NAC) was launched by IAVI in 2002 to solve a fundamental problem in HIV vaccine development: the elicitation of antibodies that can neutralize a broad range of HIV variants.Today the NAC is one of the leading sources of innovation worldwide in the study of broadly neutralizing antibodies (bNAbs) and the design of immunogens that could elicit HIV bNAbs in the human body.

During the past decade, through the efforts of the NAC and many other leading scientific collaborators, more than 200 bNAbs have been isolated from volunteers around the world. The structures of some of the most potent of these antibodies and their targets have also been solved. These discoveries are now being applied to the design of novel HIV vaccine candidates.

The NAC is headquartered at Scripps Research in La Jolla, California. Together, Scripps and IAVI employ experts in computational immunogen design, structural biology, virology, immunology, and antibody discovery.

[1]GSK proprietary AS01 adjuvant system contains QS-21 Stimulon® adjuvant licensed from Antigenics LLC, a wholly owned subsidiary of Agenus Inc. (NASDAQ: AGEN), MPL and liposomes.


The Vaccine Testing Process

The development cycle of a vaccine, from lab to clinic.

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PRECLINICAL TESTING : Scientists test a new vaccine on cells and then give it to animals such as mice or monkeys to see if it produces an immune response.

PHASE 1 SAFETY TRIALS : Scientists give the vaccine to a small number of people to test safety and dosage, as well as to confirm that it stimulates the immune system.

PHASE 2 EXPANDED TRIALS : Scientists give the vaccine to hundreds of people split into groups, such as children and the elderly, to see if the vaccine acts differently in them. These trials further test the vaccine’s safety.

PHASE 3 EFFICACY TRIALS : Scientists give the vaccine to thousands of people and wait to see how many become infected, compared with volunteers who received a placebo. These trials can determine if the vaccine protects against the coronavirus, measuring what’s known as the efficacy rate. Phase 3 trials are also large enough to reveal evidence of relatively rare side effects.

EARLY OR LIMITED APPROVAL : Many countries have procedures for providing emergency authorizations for vaccines, based on preliminary evidence that they are safe and effective. In addition, some countries such as China and Russia began administering vaccines before detailed Phase 3 trial data was made public. Experts have warned of serious risks from jumping ahead of these results.

APPROVAL : Regulators review the complete trial results and plans for a vaccine’s manufacturing, and decide whether to give it full approval.

COMBINED PHASES : One way to accelerate vaccine development is to combine phases. Some vaccines are now in Phase 1/2 trials, for example, which this tracker would count as both Phase 1 and Phase 2.

PAUSED or ABANDONED : If investigators observe worrying symptoms in volunteers, they can pause the trial. After an investigation, the trial may resume or be abandoned.


Virtual Molecules Nail Bacteria's Weapon

To understand how proteins work, biologists need to know what shapes they naturally fold into. The straightforward ways of finding out, x-ray crystallography and nuclear magnetic resonance, take as long as a year to reveal a protein's three-dimensional structure. Increasingly reliable mathematical models, however, can now predict parts of the structure much faster. In the latest computer- assisted coup, mathematicians and biologists at the Massachusetts Institute of Technology (MIT) have developed a program that predicts in milliseconds whether a protein folds into a structure called a b helix. To their surprise, they found that a protein with a b helix is like a child with a can of spray paint: It's almost surely up to no good.

“This program found a very interesting subset of proteins—whooping cough virulence factors, Helicobacter pylori toxins, ragweed pollen allergens, and so on,” says Jonathan King, a biologist on the team who specializes in protein folding. King speculates that the b helix, a long spike, is used for attaching to or penetrating cell membranes. The work is “a tremendous accomplishment,” says Peter Kim, a protein biologist who recently moved from MIT to direct Merck Research Laboratories in Rahway, New Jersey. “The bottom line is that a computer scientist has drawn attention to a class of proteins involved in human disease, which are potentially of medical significance.”

The first known b helix was reported in 1993 by Frances Jurnak, an x-ray crystallographer who now works at the University of California, Irvine. It turned up in a bacterial protein called pectate lyase, which breaks down the pectin in plants' cell walls. Since then, a handful of other proteins with b helices have been found. One of them is pertactin, made by Bordetella pertussis, the bacterium that causes whooping cough. Because it elicits a strong immune response, pertactin has been incorporated into a new vaccine against that disease. But with only 12 known examples out of 12,000 solved proteins in the Protein Data Bank, b helices remained “low on the totem pole for structural biologists,” King says.

The MIT group saw things differently. To them, the orderly structure of b helices made them ideal candidates for computational prediction. A b helix is made up of “rungs,” consisting of three b strands (flat, uncoiled pieces of protein that stack into sheets with a water-loving side and a water-repelling side). A typical helix contains from 7 to 16 triangular rungs, which twist around gradually to the right. b sheets in general are hard to predict from an amino acid sequence, because residues that are widely separated in the protein's sequence may lie in adjacent rungs. Residues that lie in adjacent b strands usually match, but the residues on the “turns” between strands need not match at all. Because the turns have unpredictable lengths, it is hard for biologists to know where to look for the matching pairs. Fortunately, in the b helix each rung contains an easily recognized landmark: a very short turn, usually only two amino acid residues long, called the T2 turn.

Bonnie Berger, Lenore Cohen, and Phil Bradley in the MIT mathematics department incorporated this information into a computer program called BetaWrap. The program first identifies a likely T2 turn and assigns a score to the adjacent regions based on the probability that they will form b strands. Then it scans farther down the sequence for strands that have a high probability of stacking well onto the two already found. The program computes this probability by analyzing hundreds of known b sheets in the Protein Data Bank, but not the 12 known b helices. Tested to see whether it could pick the known b helix-bearing proteins out of a lineup, BetaWrap scored 12 out of 12—a feat no rival program could match.

Next, Berger turned the program loose on the larger SWISS-PROT database, consisting of proteins with unknown structure. BetaWrap found hundreds of b-helix candidates, some of which scored even higher than the known b helices. When Berger showed the list to King, he was astounded to see that the top 100 candidates were all bacterial proteins—even though Berger's team had no way of telling bacterial proteins apart from mouse or human proteins. “That's when he believed us, because we produced these things that made biological sense,” Berger says. Berger announced the results at this month's meeting of the American Mathematical Society in New Orleans.

BetaWrap's predictions still must be checked by crystallography, a process that will probably take at least a year. But some researchers already plan to use the program's results as a springboard for new research. “I'm immediately going to run BetaWrap on viral genome sequences,” Jurnak says, to see whether bacteria are indeed the only source of b helices.


ACKNOWLEDGMENTS

Lisa Karanja, Orville Schell Fellow in the Women's Rights Division, researched and wrote this report.LaShawn R. Jefferson, executive director of the Women's Rights Division, and Helen Epstein, consultant, provided additional field research assistance. Joanne Csete, director of the HIV/AIDS Program Peter Takirambudde, executive director of the Africa Division Janet Fleischman, Washington director of the Africa Division LaShawn Jefferson and Joe Saunders, deputy director in the Program Office edited the report.James Ross, senior legal advisor, provided legal review.Natalie Rainer, Katherine Bowman, Andrea Holley, Veronica Matushaj, Jonathan Horowitz, and Fitzroy Hepkins provided production assistance.

The Women's Rights Division gratefully acknowledges the assistance of the many individuals, government officials, and institutions in Uganda who were instrumental in our efforts to investigate the links between domestic violence and women's vulnerability to HIV.We would like to extend particular thanks to certain individuals and nongovernmental organizations, including Debbie Kaddu-Serwadda, Dr. Seggane Musisi, Maureen Owor, Irene Kakooza, Eva Kawuma, Jessica Saboni, Hellen K. Alyek, Raising Voices, National Community of Women Living with HIV/AIDS, The AIDS Support Organisation, Action Aid-Uganda, Uganda Women's Network, Slum Aid, the Association of Uganda Women Lawyers (FIDA) , Traditional and Modern Health Practitioners Together Against AIDS, the Tororo Civil Society Network, the Mifumi Project, National Women's Organisations of Uganda, Akina Mama wa Afrika, the AIDS Information Centre, the Legal Aid Project, Isis-Women's International Cross-Cultural Exchange, Uganda Media Women Association, Law and Advocacy for Women in Uganda, Foundation for Human Rights Initiative, Association of Uganda Women Medical Doctors, Hope After Rape, Society of Women and AIDS in Africa, UNDP-Uganda, UNAIDS-Uganda, the Royal Danish Embassy, and the Royal Norwegian Embassy.Human Rights Watch also thanks the government officials who agreed to be interviewed for this report.

We extend particular thanks to Joy Namayanja for her tireless work with us in Uganda.We also wish to thank Jasmine Juteau , Elizabeth Morrow, Yasuyo Shimizu, Maya Scherer, Catherine Kihara , Denise Nieves, Julie Hassman , and Naureen Mirza for research and logistical assistance.

Human Rights Watch extends particular thanks to UWONET and Raising Voices for assistance in reviewing material.

Most of all, Human Rights Watch wishes to thank all the individuals in Uganda who agreed to be interviewed for this report.We particularly thank the courageous women who were willing to speak to us of their experiences, without whom this report would not be possible.

We also acknowledge with gratitude the financial support of Kathleen Peratis and Richard Frank, the John D. and Catherine T. MacArthur Foundation, the Ford Foundation, the Moriah Fund, the Oak Foundation, the Streisand Foundation, the Dobkin Family Foundation, and the members of the Advisory Committee of the Women's Rights Division.

Women's Rights Division

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Its Women's Rights Division was established in 1990 to monitor violence and discrimination against women throughout the world. LaShawn R. Jefferson is the executive director Janet Walsh is the deputy director Nisha Varia is a researcher Lisa Karanja is the Schell Fellow and Natalie Rainer is the associate. Kathleen Peratis is chair of the advisory committee.

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[1] Common Country Assessment of the United Nations agencies working in Uganda, Uganda: Promise, Performance and Future Challenges (Kampala: Office of the United Nations Resident Coordinator in Uganda, 2000), p. 6.

[2] Prevalence refers to the number of infected people in a given population.Incidence refers to the rate at which people become infected.

[3] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p.6.Helen Epstein, who formerly taught molecular biology at Makerere University in Kampala, wrote: "Epidemiologists conducting smaller studies of particular Ugandan populations have shown that even when prevalence is falling, incidence may still be high, or even rising.In fact, while some regions of Uganda have seen a fall in HIV incidence during the 1990s, others have seen little change."See Helen Epstein, "AIDS: The Lesson of Uganda," New York Review of Books, July 5, 2001, p. 18.

[4] The initial public awareness campaign featured roadside billboards carrying HIV/AIDS prevention messages erected across the country.

[5] Human Rights Watch interview with Joyce Namulondo, planning office, Uganda AIDS Commission, Kampala, January 16, 2003, Kampala, January 16, 2003.

[6] "Domestic violence can be defined as the use of force or threats of force by a husband or boyfriend for the purpose of coercing and intimidating a woman into submission."United Nations Centre for Social Development and Humanitarian Affairs, Strategies for Confronting Domestic Violence: A Resource Manual, U.N. Doc. ST/CSDHA/20 (1993), p. 7.The term "domestic violence" is used in this report to refer to violence against women by their (male) intimate partners.It therefore includes women who are cohabiting and women in relationships where formal customary marriage requirements have not been completed.The terms "husband" and "wife" refer to partners living in a marital state.

[7] For an overview of HIV/AIDS and women and girls, see Human Rights Watch, Suffering in Silence: The Links Between Human Rights Abuses and HIV Transmission to Girls in Zambia(New York: Human Rights Watch, 2002), chapter IV.

[8] Fifth Regional Conference on Women, "African Platform for Action," Dakar, Sngal , November 16 to 23, 1994, para. 19.

[9] "AFRICA: Interview with Stephen Lewis, U.N. Special Envoy for HIV/AIDS in Africa," IRIN Plus News, November 29, 2002, [online], http://www.irinnews.org/AIDSreport.asp?ReportID=1541&SelectRegion=Southern_Africa (retrieved April 7, 2003).

[10] Joint United Nations Programme on HIV/AIDS (UNAIDS) press release, "60 million Africans Have Been Touched By AIDS, Says UNAIDS Executive Director: AIDS has become Africa's biggest challenge," Maputo, July 10, 2003, [online], http://www.unaids.org/whatsnew/press/eng/ausummit_100703_en.html (retrieved July 22, 2003).

[11] According to UNAIDS, in 2002, 58 percent of HIV-positive adults in sub-Saharan Africa and 55 percent of HIV-positive adults in North Africa and the Middle East were women.See UNAIDS and World Health Organization (WHO), AIDS Epidemic Update, December 2002 (Geneva: UNAIDS/WHO, 2002), UNAIDS/02.46E, [online],

[12] UNAIDS/WHO, AIDS Epidemic Update.

[13] As of February 1, 1962, Uganda had 56 indigenous communities.See Third Schedule to the Constitution of the Republic of Uganda, 1995.The people of Uganda are divided into four main linguistic groups: the Bantu, the Luo , the Nilo-Hamites , and the Sudanic , each of which consists of several smaller ethnic and linguistic groups.Religion is an important factor in community life and national affairs.According to official statistics, two-thirds of the population are Christians, about 16 percent are Muslims, and the rest are animists.See Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 10.

[14] Manisuli Ssenyonjo , "The Domestic Protection and Promotion of Human Rights Under the 1995 Ugandan Constitution," Netherlands Quarterly of Human Rights, vol. 20, no. 4, December 2002, 445, p. 447.

[16] 1964 to 1971 and 1980 to 1985.

[17] For an overview of human rights developments in Uganda in 2002, see Human Rights Watch, World Report 2003 (New York: Human Rights Watch, 2003), p. 87.

[18] "Uganda: Museveni approves multipartyism ," IRINNews.org , February 19, 2003, [online],

[19] Human Rights Watch interview with Ruth Ojiambo-Ochieng , director, Isis Women's International Cross-Cultural Exchange, Kampala, December 12, 2002. For comprehensive coverage of the conflict, see Human Rights Watch's Uganda web page, http://www.hrw.org/africa/uganda.php .For a report on the abduction and recruitment of children by the LRA see Human Rights Watch, Stolen Children: Abduction And Recruitment In Northern Uganda (New York: Human Rights Watch, 2003).

[20] The Ugandan government confirmed that there are currently fifty-six districts in Uganda, although not all are functioning, and only forty-eight are "fully-fledged" districts.Human Rights Watch interview with Patrick Mutaburi , commissioner, Local Councils Development,Ministry of Local Government, Kampala, January 17, 2003, and Human Rights Watch telephone interview with Tayebwa Katureebe , second secretary, Embassy of the Republic of Uganda, Washington D.C., May 28, 2003.

[21] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 12.

[23] UNDP Human Development Report 2002, n.d . (New York: UNDP, 2002),p. 1, [online], http://hdr.undp.org/reports/global/2002/en/pdf/HDR%20PR_HDI.pdf (retrieved April 11, 2003).The Ugandan government's Poverty Eradication Action Plan (PEAP) forms the central policy framework for partnership between the government, the U.N., donor organizations, and civil society for addressing poverty and development.The PEAP also forms the foundation for Uganda's Poverty Reduction Strategy Paper. The government initiated the Uganda Participatory Poverty Assessment Project (UPPAP)in 1988, involving intensive consultations in thirty-six rural and urban communities, and the municipality of Kampala.

[24] UNDP, Uganda Human Development Report 2000: Unemployment and Poverty, (Kampala: UNDP, 2000),para. 7.5.

[25] Ministry of Gender, Labour and Social Development, "The Convention on the Elimination of All Forms of Discrimination against Women, Third Country Status Report," December 1999, (Kampala: MGLSD, 1999), p. 2.

[26] Uganda AIDS Commission, "The HIV/AIDS Epidemic: Facts and Figures, May 2002," [online], http://www.aidsuganda.org/anylisis_2002.htm (retrieved April 12, 2003).

[27] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 41. Article 237 of the constitution and section 3 of the 1998 Land Act provide that land in Uganda belongs to Ugandan citizens and vests in accordance with four land tenure systems, namely: Customary Land Tenure, Freehold, and Leasehold, and Mailo (peculiar to the Buganda , the Mailo system was established by article 15 of the 1900 Buganda Agreement-also known as the Uganda Agreement-between Britain and the Kingdom of Buganda ).Article 237(4)(a) of the constitution recognizes customary tenure.Article 237(4) of the constitution also provides that tenants on customary land can acquire a certificate of customary ownership and convert their holding to a freehold title.Art. 237(8) of the constitution guarantees security of tenure to tenants on registered land who can acquire a certificate of occupancy.The Land Act recognizes the right to hold communal land.For general information on women and the land reform process, see Gender Perspectives in the Land Reform Process in Uganda, (Kampala: Uganda Land Alliance, 2002).

[28] UNDP, Uganda Human Development Report, 2000, para. 3.10.

[30] Republic of Uganda, "Summary of Background to the Budget 2001/02, Uganda Poverty Reduction Strategy Paper

Progress Report 2002," (Kampala: Ministry of Finance, Planning and Economic Development, 2000), p. 11, [online], http://poverty.worldbank.org/files/Uganda_PRSP_APR.pdf (retrieved April 12, 2003).

[31] UNDP, Uganda Human Development Report, 2000, para. 6.4.In 1997 Uganda became the first country in the world to be given debt relief-equivalent to U.S.$71 million-by the "Paris Club" (a grouping of Western state banks and private donors and financiers).Funds have been used to support projects such as water supplies, health care, and education.In May 2000, Uganda was also the first country to benefit from a new enhanced Heavily Indebted Poor Countries (HIPC) initiative, which provided debt relief of an additional U.S.$45-50 million per year for the first three years.

[32] UNDP, Uganda Human Development Report, 2000, para. 6.3.

[33] The Judicature Act, 1967, sec. 16, Laws of Uganda.

[34] MGLSD, "Third Country Status Report," p. 4.

[36] Constitution of the Republic of Uganda, 1995, art. 2.

[37] Republic of Uganda, Courts of Judicature, [online], http://www.judicature.go.ug/org.php (retrieved April 11, 2003).The Courts of Judicature also include the Court of Appeal and the High Court. Qadhi courts, which administer Islamic law (Shari'a) in family matters are included as subordinate courts.See Republic of Uganda, "Courts of Judicature."The Court of Appeal doubles as the Constitutional Court.See MGLSD, "Third Country Status Report," p. 6.Magistrate Grade II courts also function as Family and Children's Courts.See the Children's Statute, secs .14 and 16, 1996.See also MGLSD, "Third Country Status Report," p. 5.

[38] During the guerrilla war of the early 1980s, the NRM formed locally elected, nine-person committees known as resistance councils ( RCs ) in the areas it controlled.The enactment of the Resistance Committees (Judicial Powers) Statute 1987 resulted in the administrative units being vested with judicial powers (now referred to as local council courts since the passing of the 1995 Constitution and the Local Government Act of 1997).

[39] LC4 and LC5 are largely administrative.

[40] Where a person dies without making a will.

[41] Republic of Uganda, "Summary of Background to the Budget 2001/02, Uganda Poverty Reduction Strategy Paper Progress Report 2002," p. 43.

[42] Constitution of the Republic of Uganda, 1995, art. 180(2)(b).Uganda Local Government Act, 1997, secs . 11(e), 24(1)(e), 24(2)(e), 24(3)(e), 24(4)(e). An amendment to section 2 of the Local Government Act, adopted on June 7, 2001, provides as an additional objective, "[T]o establish affirmative action in favor of groups marginalized on the basis of gender, age, disability or any other reason created by history, tradition or custom, for the purpose of addressing imbalances which exist against them."

[43] Lawyers are not allowed in the LC courts but may provide their clients with advice beforehand.

[44] Republic of Uganda, "Summary of Background to the Budget 2001/02, Uganda Poverty Reduction Strategy Paper Progress Report 2002," p. 42.

[45] United Nations Children's Fund (UNICEF), Girls' Education In Uganda, n.d .,UNICEF/HQ99-0136/Pirozzi, p. 1, [online], http://www.unicef.org/programme/girlseducation/action/ed_profiles/Ugandafinal.PDF (retrieved April 12, 2003).The increased enrollment has overburdened the system and contributed to a decline in the quality of education offered.In 2000, the government admitted: "It is generally agreed that the quality of education in Uganda declined seriously between the mid-1970s and the late 1980s, and the increased enrollment is now straining the system. . . . The heavily burdened primary schooling system cannot meet the immediate demands for classrooms, teachers, and teaching/learning materials."See Republic of Uganda, "Uganda's Poverty Eradication Action Plan, Summary And Main Objectives," Uganda Poverty Reduction Strategy Paper, (Kampala: Ministry of Finance, Planning and Economic Development, 2000), p. 10, [online], http://poverty.worldbank.org/files/Uganda%20IPRSP.pdf (retrieved April 12, 2003).

[46] The total number of girls enrolled in primary school as a proportion of the total number of primary school age girls surveyed.

[47] UNICEF, Girls' Education In Uganda, p. 1.

[49] Formal education in Uganda is divided into three major cycles:primary school (seven years), secondary school (six years), and tertiary (two to five years).

[50] Senior 4 is approximately e quivalent twelve years combined primary and secondary education and corresponds to the GCE (General Certificate of Education, now GCSE) Ordinary level (O-level) grade.The GCE is an internationally recognized qualification at secondary level.O-level examinations are usually taken after five years of secondary education.

[51] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 29.

[52] MGLSD, "Third Country Status Report," p. 37.In 1990, the government added a 1.5-point "bonus" to the scores of female qualifying candidates for admission to university to increase their numbers.The government has also embarked upon functional adult literacy programs.See the Status Report, pp. 39 and 40.

[53] UNDP, Uganda Human Development Report 2000, para. 3.5.

[54] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 22.

[55] Resource Centre, Ministry of Health, Uganda, "Statistical Abstract," June 2001, (Kampala: Ministry of Health, 2001), p. 7.In the same year, the U.N. calculated that there were 1,500units, of which the government operated 60 percent.The remaining 40 percent were run by NGOs or are privately owned and operated. Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 23.

[56] UNDP, Uganda Human Development Report, 2000, para. 3.10.

[57] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 23.

[59] Gerard Bodeker et al., "A Regional Task Force on Traditional Medicine and AIDS," The Lancet, April 8, 2000, vol. 355, p. 1284.Reproduced in its entirety under the World Bank, IK Notes, "Traditional Medicine and AIDS," vol. 26, November 2000, p. 1,[online], http://www.worldbank.org/afr/ik/iknt26.pdf (retrieved April 12, 2003).

[60] Uganda AIDS Commission Secretariat, "Twenty Years of HIV/AIDS in the World-Evolution of the Epidemic and Response in Uganda," (Kampala: UAC Secretariat, June 2001), p.2.

[62] UNAIDS, UNAIDS HIV Drug Access Initiative: Pilot Phase, Best Practice Digest, n.d ., [online], http://www.unaids.org/bestpractice/digest/files/drugaccess.html (retrieved May 20, 2003).The Uganda Ministry of Health-UNAIDS HIV/AIDS Drug Access Initiative estimates the number at 1.5 million.See Uganda Ministry of Health/UNAIDS-Uganda/CDC, "Preliminary Report: Uganda Ministry of HealthUNAIDS HIV/AIDS Drug Access Initiative," August 1998-March 2000, [online], http://www.unaids.org/publications/documents

(retrieved May 20, 2003).A U.N. 2002 update estimates the number of adults and children living with HIV/AIDS at the end of 2001 at 600,000.See UNAIDS/WHO, Epidemiological Fact Sheets on HIV/AIDS and Sexually Transmitted Infections, Uganda, 2002 Update, p.2, [online], http://www.unaids.org/hivaidsinfo/statistics/fact_sheets/pdfs/Uganda_en.pdf (retrieved May 28, 2003).

[63] "Global Challenges:Ugandan President Says HIV/AIDS Costs Uganda More Than $700 Million Each Year," Kaisernetwork.org , November 19, 2002, [online], http://www.kaisernetwork.org/daily_reports/ rep_index.cfm?DR_ID=14659 (retrieved May 13, 2002).

[64] MGLSD, "Third Country Status Report," p. 51.

[65] AIDS Information Centre, "HIV Prevalence by Age Groups among adult 1st time testers," n.d ., (Kampala: AIC).

[66] Human Rights Watch interview with Dr. Lukanika-Hitimana , executive director, AIDS Information Centre, Kampala, December 11, 2002.

[67] Uganda AIDS Commission, "The HIV/AIDS Epidemic: Facts and Figures," (Kampala: UAC, 2002), [online], http://www.aidsuganda.org/anylisis_2002.htm (retrieved March 17, 2003).

[68] See for example, WHO, Uganda reverses the tide of HIV/AIDS, Health, A Key to Prosperity, Success Stories in Developing Countries, [online],http://www.who.int/inf-new/aids2.htm (retrieved June 24, 2003).WHO reports, "Since 1993, HIV infection rates among pregnant women, a key indicator of the progress of the epidemic, have been more than halved in some areas and infection rates among men seeking treatment for sexually transmitted infections have dropped by over a third."According to one government official, President Museveni's commitment to fighting HIV/AIDS dates back to 1986, when almost one third of his top military officers training in Cuba tested positive for HIV.Human Rights Watch interview with Miria Matembe, minister of ethics and integrity, Kampala, January 13, 2003.

[69] Human Rights Watch interview with Miria Matembe, minister of ethics and integrity, Kampala, January 13, 2003.

[70] Human Rights Watch interview with Pastor Wilberforce Owori, Tororo, December 16, 2002.

[71] STD/AIDS Control Programme, "HIV/AIDS Surveillance Report," (Kampala: Ministry of Health, 2002), p. 19.

[72] Uganda AIDS Commission Secretariat, "Twenty Years of HIV/AIDS in the World," p. 2.

[74] Uganda AIDS Commission, National AIDS Documentation Centre, "Uganda HIV/AIDS Control Project (UACP)," n.d ., [online], http://www.aidsuganda.org/aids_control.htm (retrieved February 17, 2003).

[75] Uganda AIDS Commission, National AIDS Documentation Centre, "Mandate and Background," n.d .,[online], http://www.aidsuganda.org/uac.htm (retrieved February 17, 2003).

[76] Human Rights Watch interview with Dr. Sheila Ndyanabangi, mental health programme , Ministry of Health, Kampala, January 14, 2003.

[78] Development partners include the World Bank the World Health Organisation (WHO) the European Union the British Department for International Development (DFID) the Danish Agency for Development Assistance (DANIDA) the Swedish International Development Cooperation Agency (SIDA) and the Italian, German, French, Dutch, and Japanese governments.See Uganda AIDS Commission Secretariat, "Twenty Years of HIV/AID in the World," p. 2.According to UNAIDS Uganda Country Advisor Reuben Delprado , future UNAIDS efforts will incorporate a focus on resource management, access to treatment, and the collection, synthesis, and sharing of strategic information.Human Rights Watch interview with Reuben Delprado , Uganda country advisor, UNAIDS, Kampala, January 12, 2003. Daouda Tour , director of UNDP-Uganda told Human Rights Watch: "UNDP is well placed to look at women's rights.In the U.N. system we are looking at a human rights approach.We want to be the cop that comes before the fine." Human Rights Watch interview with Daouda Tour , resident coordinator/U.N. resident representative, UNDP-Uganda, Kampala, January 14, 2003.Donors explained to Human Rights Watch that they include a focus on HIV/AIDS and gender in other programming. Human Rights Watch interviews with H.E. Flemming Bjrk Pedersen, Ambassador, Royal Danish Embassy, Kampala, January 14, 2003, and H.E. Tore Gjs , Ambassador, Royal Norwegian Embassy, Kampala, January 16, 2003.

[79] The Global Fund to Fight AIDS, Tuberculosis & Malaria, "Fact Sheet," n.d ., [online], .org/proposals/round1/fsheets/uganda.html (retrieved July 25, 2003).

[80] On January 28, 2003, President George W. Bush announced the Emergency Plan for AIDS Relief, a five-year, U.S.$15 billion initiative touted to turn the tide in the global effort to combat the HIV/AIDS pandemic.United States Department of State, International Information Programs, f act sheet, "White House Outlines Bush HIV/AIDS Programs for Africa," January 29, 2003, [online], http://usinfo.state.gov/regional/af/usafr/a3012901.htm (retrieved April 7, 2003).

[81] The amendment offered by Rep. Joseph Pitts requires one-third of HIV/AIDS prevention funds to promote "abstinence-until-marriage."For a general discussion on federally funded abstinence-only programs in the United States, see Human Rights Watch, Ignorance Only: HIV/AIDS, Human Rights And Federally Funded Abstinence-Only Programs In The United States, Texas: A Case Study, (New York: Human Rights Watch, 2002).Sally Ethelston , vice president of communications at Population Action International, stated: "This amendment completely denies the reality of AIDS in Africa, where women are disproportionately impacted by the spread of HIV. Gender inequities frequently leave them powerless to 'just say no' to sex, and unable to know whether their partners are being truly monogamous. Not to mention the fact that men in sub-Saharan Africa have access on average to fewer than five condoms per year."See Population Action International, "Glo bal AIDS Bill Passage Good News But Marred by Abstinence-Until-Marriage Clause," May 1, 2003, [online], http://www.populationaction.org/news/press/news_050103.html (Retrieved May 13, 2003).Physicians For Human Rights U.S. Policy Director Holly Burkhalter made a similar point: "Funding abstinence programs as part of an integrated prevention strategy can be effective. Funds for stand-alone programs deny best public health practices by failing to recognize the value of condoms the only existing physical barrier to sexual transmission of the disease. By diverting AIDS money to ineffective programs, money will be wasted, and more importantly, lives will be lost." "Physicians for Human Rights Welcomes Passage of AIDS Bill: Cautions against Emphasis on Abstinence-Only," May 1, 2003, [online], http://www.phrusa.org/campaigns/aids/release050103.html (retrieved May 13, 2003).International women's groups have welcomed an amendment aimed at providing financial assistance "for the purpose of encouraging men to be responsible in their sexual behavior, child rearing, and to respect women," and calls for programs that address sexual violence and coercion, including wife inheritance and polygamy.The amendment was offered by Rep. Joseph Crowley.See Juliet Eilperin , "Senate Passes AIDS Measure for Africa:Provision Would Promote Sexual Responsibility, Respect for Women Among Men," Washington Post, May 16, 2003, [online], http://www.sahims.net/batchfiles_web/reg/05/Senate%m (retrieved July 19, 2003).

[82] In May, Dr. Paul Zeitz , executive director of the Global AIDS Alliance stated: "Sadly, the President, and top Congressional decision-makers like Senator Frist and Speaker Hastert seem to have little intention of actually providing this level of funding. They are playing a cruel joke on countries battling for their very survival."Global AIDS Alliance, "AIDS Bill Is a 'Bad Check' that will Bounce: Bill Also Fails to Mandate Vitally Needed Debt Relief," May 16, 2003, [online], http://www.globalaidsalliance.org/press051603.html (retrieved May 19, 2003).

[83] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 30.

[84] For a general discussion on domestic violence globally, see Human Rights Watch, The Human Rights Watch Global Report on Women's Human Rights (New York: Human Rights Watch, 1995), chapter 6.Additional reports on domestic violence in specific countries include: Human Rights Watch, Sacrificing Women to Save the Family? Domestic Violence in Uzbekistan (New York: Human Rights Watch, 2001) Human Rights Watch, Seeking Protection: Addressing Sexual and Domestic Violence in Tanzania's Refugee Camps (New York: Human Rights Watch, 2000) Human Rights Watch, Crime or Custom?Violence Against Women in Pakistan (New York: Human Rights Watch, 1999) Human Rights Watch, (Russia) Too Little, Too Late: State Response to Violence Against Women (New York: Human Rights Watch, 1997) Human Rights Watch, Violence Against Women in South Africa: The State Response to Domestic Violence and Rape (New York: Human Rights Watch, 1995) and Human Rights Watch, Violence Against Women And The Medico-Legal System (South Africa) (New York: Human Rights Watch, 1997).

[85] Law & Advocacy for Women Uganda, "Project Report on the Domestic Violence Study," second Edition,(Kampala: LAW-U, 2001), p. 59.

[86] Innocenti Research Centre, Domestic Violence Against Women and Girls, June 2000, Innocenti Digest no. 6,(Italy: UNICEF,2000), p. 5.

[87] Dan Kaye, "Risk Factors, Nature and Severity of Domestic Violence among Women Attending Antenatal Clinics in Mulago Hospital, Kampala, Uganda," Central African Journal of Medicine, vol. 48, no. 5/6, May/June 2001, p. 64.Human Rights Watch interview with Dan Kaye, Department of Obstetrics and Gynaecology, Makerere University Medical School, Kampala, January 15, 2003.

[88] These figures did not include reports of domestic violence made in December as these were not available at the time of our interview.

[89] Human Rights Watch interview with Helen Alyek, superintendent, Child and Family Protection Unit, Nsambya Police Station, December 19, 2002.

[90] Established by the United Nations to monitor compliance with the Convention on the Elimination of All Forms of Discrimination against Women (CEDAW).

[91] CEDAW Committee Draft Report, Consideration of Reports of State Parties, Uganda, (advance unedited version), Third Periodic Report, (Exceptional session, August 5 to 23, 2002), U.N. Doc. CEDAW/C/ 2002/EXC/CRP.3/Add.3/Rev 1, para. 23,[online],

http://www.un.org/womenwatch/daw/cedaw/cedawExsess/ConcComments/ConComUganda.PDF(retrieved December 1, 2002).

[92] Threatening Violence, sec. 76 Common Assault, sec. 227 Assault Occasioning Bodily Harm sec. 228 Grievous Harm, sec. 212.The Penal Code, (Chapter 106), Laws of Uganda, (1978 reprint).

[93] The presumption that a spouse consents to sex with their partner through the act of marriage.

[94] LAW- U,"Project Report on the Domestic Violence Study," p. 58.

[96] Specioza Kazibwe resigned from the post of vice-president in May 2003.See "Uganda: Mixed reaction to vice-president's resignation," IrinNews.org , Nairobi, May 22,2003,[online], Http://www.irinnews.org/report.asp?ReportID=34256 (retrieved May 22, 2003).

[97] For an example on the debate surrounding Kazibwe's allegations, see "Should the VP have remained silent?" The New Vision, March 19, 2002, [online], http://www.newvision.co.ug/detail.php?mainNewsCategoryId=9&news CategoryId =31&newsId=48895 (retrieved May 27, 2003).

[98] The Coalition Against Gender Violence, Population Secretariat, Ministry of Finance and Economic Planning, "An Assessment of Gender Violence In Apac and Mbale Districts of Uganda, 1999 to 2000" (Kampala: Coalition Against Gender Violence, 2000), p. 80.

[99] CEDAW Committee Draft Report, Consideration of Reports of State Parties, Uganda, para. 7.

[100] Human Rights Watch refers to "polygyny" as "the state or practice of having more than one wife or female mate at one time" rather than "polygamy," being a marriage in which a spouse of either sex may have more than one mate at the same time.However, we may quote interviewees using the blanket term "polygamy."

[101] CEDAW Committee, Concluding Comments, Consideration of Reports of State Parties, para. 17.

[102] The Uganda Law Reform Commission, established in 1990 with a mandate to formulate and assist in implementing laws that adhere to international standards and the Constitution, drafted the Domestic Relations Bill to address inequities in Ugandan laws on issues of domestic relations. The Sexual Offences Bill, drafted in 1999, came about partly as a reaction to proposals for lowering the age of consent to provide for earlier marriages of girls. Wary of overloading the Domestic Relations Bill, the Law Reform Commission proposed the drafting of an alternative bill relating specifically to domestic violence.

[103] Human Rights Watch interview with Miria Matembe, minister of ethics and integrity, Kampala, January 13, 2003.

[104] Constitution of the Republic of Uganda, 1995, arts. 78 and 180.

[105] United Nations Press Release, "Landmark constitution creates enabling environment for women, Ugandan minister tells committee," Committee on the Elimination of Discrimination against Women 575th & 576th Meetings (AM & PM), August 9, 2002, WOM/1355,[online], http://www.un.org/news/press/docs/2002/wom1355.doc.htm (retrieved December 1, 2002).

[106] Uganda Women's Network (UWONET), "Issues Paper On Outstanding Areas of Priority to Gender Equality" (Kampala: UWONET, November 2002), p. 4.

[107] MGLSD, "Third Country Status Report," p.8: "The women's council is a six-tier structure beginning at the village level, through the district, up to the national level.The councils are local fora for women through which they are mobilized for civic and development activities in their local areas."

[108] Ugandan law recognizes five types of marriages: civil, Christian, Hindu, Muslim, and customary.Apart from numerous unwritten customary laws, the main statutory framework relating to marriage and divorce includes: the Marriage Act (Cap. or chapter 211, Laws of Uganda), Marriage of Africans Act (Cap. 212, Laws of Uganda), the Marriage and Divorce of Mohammedans Act (Cap. 213, Laws of Uganda) governing all marriages and divorces between Muslims, the Hindu Marriage and Divorce Act (Cap. 214, Laws of Uganda), and the Divorce Act (Cap. 215, Laws of Uganda). The Customary Marriages Registration Decree, 1973, (Decree No. 16), provides for a uniform system of registration of customary marriages.

[109] Sylvia Tamale, "Law Reform and Women's Rights in Uganda," East African Journal of Peace and Human Rights, vol. 1:2, 1993, p. 170.

[110] The practice of widow inheritance originally arose as a social institution designed for men to take responsibility for their dead brother's children and his household.

[111] Sylvia Tamale, "Law Reform and Women's Rights in Uganda," p. 177.

[112] The land management hierarchy includes the Uganda Land Commission, which is responsible for all government land, district land boards, and land committees in each parish, gazetted urban areas or division in the case of Kampala that function as advisory bodies to the District Land Boards.Under the 1998 Land Act, jurisdiction over customary land cases passed from local council and magistrates' courts to district and sub-county land tribunals.One or both parties may still invite traditional authorities to hear their matter.Land Act, 1998, sec. 89.Section 81(2) of the Land Act provides that at least one of the members of the Land Tribunals at the sub-county level must be a woman.However, there is no such stipulation for District Land Tribunals.

[113] MGLSD, "Third Country Status Report," p. 44.

[114] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p. 42.

[115] MGLSD, "Third Country Status Report," p. 44.

[116] Adopted June 30, 1998 and enacted July 2, 1998.

[117] Where two or more people have a joint interest in property.The land may be held jointly, whereby land is registered in the names of two or more people.On the death of one owner, full ownership vests in the surviving owner. The land may also be held in common, whereby the owners have separate interests in the same property, and their heirs inherit their share.

[118] Gerald Businge , "Did women activists tactfully sneak co-ownership into the new Land Bill?" The New Vision, July 1, 2003, [online], http://www.newvision.co.ug/detail.php?mainNewsCategoryId=9&newsCategoryId=31&newsId=143888 (retrieved July 2, 2003).Section 39(a) is reported to protect the interests of spouses in land on which the family "ordinarily resides" or land on which both or all spouses "ordinarily reside and derive sustenance."Each spouse now has the right to give or withhold his or her consent on any transaction on family land.Some activists argue that failing to provide for co-ownership of land particularly as it will exclude family members who do not formally register their interests, weakens the clause.E-mail from Uganda Land Alliance to Human Rights Watch, May 30, 2002.

[119] "President Raps Bill," The New Vision, July 22, 2003, published July 16, 2003,[online], http://www.newvision.co.ug/detail.php?mainNewsCategoryId=8&newsCategoryId=13&newsId=147159.President Museveni reportedly opposes the "decentralization of land issues."

[120] Republic of Uganda, "Uganda's Poverty Eradication Action Plan, Summary And Main Objectives," p. 11.The National Agricultural Advisory Services (NAADS) is one of the seven components under the Plan for Modernization of Agriculture (PMA).A semi-autonomous body formed under the NAADS Act of June 2001, its mandate is to develop a demand driven, farmer-led agricultural service delivery system targeting poor subsistence farmers, with, inter alia, anemphasis on women. The Ministry of Water, Lands and Environment, the Ministry of Finance, the Law Reform Commission, the Uganda Land Alliance, and Makerere University developed a Land Sector Strategic Plan 2001-2011 (LSSP) for the implementation of sector-wide reforms, including implementation of the Land Act.The final draft was issued in November 2001.The LSSP is intended to guide the management and use of Uganda's land resources and highlights co-ownership of family land, the amendment of discriminatory inheritance laws, and strengthening women's land rights generally as priorities for reform.

[121] For further information on intimate partner violence and health, see WHO, World Report on Violence and Health, (Geneva: WHO, 2002), chapter 4, [online], http:www5.who.int/violence_injury_prevention/download.cfm?id

=0000000582 (retrieved June 2, 2003).For information on intimate partner violence in connection with voluntary counseling and testing, see Suzanne Maman et al, "HIV and Partner Violence: Implications for HIV Voluntary Counseling and Testing Programs in Dar es Salaam, Tanzania," the Horizons Project, (implemented by the Population Council, the International Center for Research on Women, International HIV/AIDS Alliance Program for Appropriate Technology in Health, and the University of Alabama at Birmingham Tulane University), [online] http://www.popcouncil.org/pdfs/horizons/vctviolence.pdf (retrieved June 2, 2003).

[122] Helen Epstein, "AIDS: The Lesson of Uganda," p. 21.

[123] Human Rights Watch interview with Hadija Namaganda, Iganga, January 11, 2003.As noted above, the real names of women who provided accounts of their experiences with domestic violence and HIV/AIDS are not used in this report unless otherwise indicated

[124] Human Rights Watch interview with Dr. Seggane Musisi, Kampala, January 7, 2003.

[125] The AIDS Support Organisation, [online], http://www.taso.co.ug/index.htm (retrieved March 31, 2003).

[126] Human Rights Watch interview with Erasmus Ochwo, counselor, TASO, Tororo, December 17, 2002.

[127] Human Rights Watch interview with Dr. Sheila Ndyanabangi, mental health program, Ministry of Health, Kampala, January 14, 2003.Helen Epstein wrote, "Indeed, those most at risk of HIV infection in Uganda now are married women who have sex only with their husbands."See Helen Epstein, "AIDS: The Lesson Of Uganda," p. 19.

[128] Human Rights Watch interview with Jackie Asiimwe-Mwesige, coordinator, UWONET, December 14, 2002.

[129] Human Rights Watch interview with Lydia Mbakile, Iganga, January 11, 2003.

[130] Human Rights Watch interview with Joyce Namulondo, planning office, Uganda AIDS Commission, Kampala, January 16, 2003.A Ugandan government health survey conducted from 2000 to 2001, found that the "use of condoms among women with noncohabiting partners was high especially among those with secondary education (61%) and those in urban areas (58%)."STD/AIDS Control Programme, "HIV/AIDS Surveillance Report" (Kampala: Ministry of Health, 2002), p. 19.

[131] Tibegwya was not sure of the precise year in which she got married, but knew that it occurred when the Kabaka , the king of the Baganda, went into exile. Date obtained from Reuters AlertNet [online], http://www.alertnet.org/thefacts/countryprofiles/220795?version=1 (retrieved April 2, 2003).

[132] Human Rights Watch interview with Masturah Tibegwya, Luwero, December 18, 2002.

[133] Human Rights Watch interview with Margaret Namusisi, Iganga, January 11, 2003.

[134] Human Rights Watch interview with Sara Kisakye, Naguru , January 15, 2003.

[135] Human Rights Watch interview with Khadija Nankwanga, Iganga, January 11, 2003.

[136] "Re-infection is a term used to describe a new or secondary infection by a virus that has already infected a person."See Project Inform, "Re-Infection: Is It a Concern for People Living With HIV?," The Body: An AIDS and HIV Information Resource, [online], http://www.thebody.com/pinf/jan03/reinfection.html (retrieved May 19, 2003).The possibility that a person living with HIV/AIDS could be reinfected with the same strain of HIV or infected with two strains at the same time has been a matter of controversy among AIDS experts for some time.In 2002, however, an influential editorial in the New England Journal of Medicine by Dr. Bruce Walker of Harvard University and the Massachusetts General Hospital reviewed available evidence and concluded that such reinfection was not only possible but convincingly documented in several cases.See Bruce Walker, "HIV-1 Superinfection -A Word of Caution," New England Journal of Medicine, vol. 347, no. 10, pp. 756-758, September 5, 2002.Even before this development, many AIDS education programs in developed and developing countries included warnings of the possibility of HIV reinfection.

[137] Human Rights Watch interview with Joy Kobushingye, Mulago, January 9, 2003.

[138] Human Rights Watch interview with Margaret Namusisi, Iganga, January 11, 2003.

[139] The risk of HIV infection in unprotected sex becomes heightened as a result of the vaginal lacerations and abrasions that often accompany sexual violence.

[140] Michael A. Koenig et al, "Domestic Violence in Rural Uganda: evidence from a community-based study," Bulletin of the World Health Organization 2003 81(1), p. 58, [online], http://www.who.int/bulletin/pdf/2003/bul-1-E-2003/81(1)53-60.pdf (retrieved April 7, 2003).

[141] Human Rights Watch interview with Ada Rose Luba, Tororo, December 17, 2002.

[142] Human Rights Watch interview with Grace Nabatanzi, Naguru , January 15, 2003.

[143] Banyarwanda (pl. of Munyarwanda), one of the largest groups in Uganda, moved north from Rwanda for economic or political reasons. Speakers of Kinyarwanda , some Banyarwanda are found farming in regions of Uganda adjacent to Rwanda while others form part of the urban, salaried elite.

[144] Human Rights Watch interview with Amina Kabayondo, Mulago, January 9, 2003.

[145] Human Rights Watch interview with Jacqueline Nakitende, Naguru , January 15, 2003.

[146] Human Rights Watch interview with Esther Nanono, Entebbe, December 13, 2002.

[147] Human Rights Watch interview with Rebecca Samanya, Luwero, December 18, 2002.

[148] Human Rights Watch interview with Barbara Nassozi, Nakulabye, January 15, 2003.

[149] Real name used at her specific request.

[150] Human Rights Watch interview with Berna Alupo, Pallisa, January 10, 2003.

[151] In Uganda, prenatal clinics are referred to as "antenatal clinics," and prenatal care as "antenatal care."

[152] Dr. Hitimana-Lukanika is the executive director of the AIDS Information Centre, established in February 1990 to provide anonymous, voluntary, and confidential HIV testing and counseling services.He confirmed that they do not require women to provide letters of approval from spouses at AIC centers.E-mail message from Dr. Hitimana-Lukanika to Human Rights Watch,May 28, 2003.

[153] Human Rights Watch interview with Mutebi Musa Takamalirawo, Kawempe office, January 13, 2003.

[154] Human Rights Watch interview with Alice Namagembe, Entebbe, December 13, 2002.

[155] Human Rights Watch interview with Lucy Akurut, Pallisa, January 10, 2003.

[156] Human Rights Watch interview with Barbara Nassozi, Nakulabye, January 15, 2003.

[157] A common viral infection experienced by people living with HIV/AIDS.

[158] Human Rights Watch interview with Rebecca Samanya, Luwero, December 18, 2002.

[159] Professor Florence Mirembe , head of Obstetrics and Gynaecology at Mulago Hospital, confirmed that prenatal patients are provided with the option of being tested for HIV and that the tests are administered solely at the request of the patient.Human Rights Watch telephone interview with Professor Florence Mirembe , head, Obstetrics and Gynaecology, Mulago Hospital, May 28, 2003.

[160] Human Rights Watch interview with Dr. Seggane Musisi, Kampala, January 7, 2003.

[161] Human Rights Watch interview with Dr. Hafsa Lukwata, Association of Uganda Women Medical Doctors (AUWMD), Kampala, December 19, 2002.

[162] Human Rights interview with Jane Nabulya, Pallisa, January 10, 2003.

[163] According to the WHO Technical Consultation on Behalf of the UNFPA/UNICEF/WHO/UNAIDS Inter-Agency Task Team on Mother-to-Child Transmission of HIV held in Geneva in October 2000, the prevention of mother-to-child transmission of HIV should be included in the minimum standard package of care for HIV-positive women and their children.A joint UNAIDS/WHO press release outlined the policy on breastfeeding and nevirapine:"An HIV-infected women should receive counseling, which includes information about the risks and benefits of different infant feeding options, and specific guidance in selecting the option most likely to be suitable for her situation. The final decision should be the woman's and she should be supported in her choice. For HIV-positive women who choose to breastfeed, exclusive breastfeeding is recommended for the first months of life, and should be discontinued when an alternative form of feeding becomes feasible."See Joint UNAIDS/WHO Press Release, "Preventing Mother-to-Child Transmission: Technical Experts Recommend Use of Antiretroviral Regimens Beyond Pilot Projects," Geneva, October 25, 2000, [online], http://www.who.int/reproductive- health/ rtis /MTCT/documents/ press_release_arv_25_10_00/Press_ARV-25-10-00.en.html (retrieved June 3, 2003).

[164] At a conference held in April of 2003, Dr. Phillipa Musoke the head of Makerere University's Paediatrics Department and a pediatrician at Mulago Hospital reportedly stated: "In our society when a baby cries, the husband, aunties, uncle, and in-laws tell the mother to breastfeed it.There is no way she is going to tell them she cannot because she has HIV/AIDS. The nurses themselves keep shouting to the mother to breastfeed her baby when it cries. There are so many pressures on the HIV/AIDS positive mother."See Lillian Nalumansi , "HIV mums pressured to breastfeed their babies," TheNew Vision, April 21, 2003, [online], http://www.newvision.co.ug/detail.php?

(retrieved May 19, 2003).A recent article in The Lancet quotes Francis Mmiro , chairman of the technical committee for the prevention of mother-to-child HIV transmission in Uganda, as stating that 61percent of the HIV-positive mothers who attended prenatal clinics at the National Referral Hospital, Mulago, choose to breastfeed even after being informed that HIV can be transmitted through breastfeeding.Saul Onyango , the medical officer in charge of prevention of mother-to-child HIV transmission, is quoted as estimating that as many as 80 percent of rural HIV-positive mothers choose to breastfeed.See Charles Wendo , "Most Ugandan HIV-positive mothers insist on breastfeeding," The Lancet, vol. 358, August 25, 2001, [online], http://pdf.thelancet.com/pdfdownload?uid=llan.358.9282.news.17420.3&x=x.pdf (retrieved May 19, 2003).The MTCT-Plus Initiative, in which the mother and her family continue to receive antiretroviral treatment after delivery, is based at Columbia University's Mailman School of Public Health and supported by a coalition of nine foundations. Dr. Peter Mugyenyi, director of the Joint Clinical Research Center in Uganda, expressed the view that if sufficiently funded, the program should be effective in decreasing mother-to-child transmission of HIV and should contribute significantly to the prevention of HIV transmission generally.Human Rights Watch telephone interview with Dr. Peter Mugyenyi, director, Joint Clinical Research Centre, Kampala, May 29, 2003, and e-mail from Dr. Mugyenyi to Human Rights Watch, June 2, 2003.

[165] Emily Bass, "Is There a Role for Vaccines in Protecting Infants Against HIV in Breast Milk?,"International AIDS Vaccine Initiative Report: Women & AIDS Vaccines, vol. 5 no. 8, July-September 2001, [online], http://www.iavi.org/reports/259/breastfeeding.htm (retrieved May 20, 2003).

[166] Bertil Lindblad, deputy director UNAIDS, Forty-Seventh Session of the Commission on the Status of Women, New York, March 5, 2003, [online], http://www.unaids.org/whatsnew/speeches/eng/47thcsw%5F050303%5Fen.html (retrieved May 19, 2003).

[167] Human Rights Watch interview with Sandra Kyagabe, counselor, NACWOLA, Kampala, December 19, 2002.

[168] Human Rights Watch interview with Alice Namagembe, Entebbe, December 13, 2002.

[169] Human Rights Watch interview with Erasmus Ochwo, TASO, Tororo, December 17, 2002.

[170] Human Rights Watch interview with Josephine Kalule , program manager, AIDS Information Centre, Kampala, December 11, 2002.

[171] Human Rights Watch interview with Erasmus Ochwo, TASO, Tororo, December 17, 2002

[172] Human Rights Watch interviews with Dr. Lukanika-Hitimana director AIC, and Josephine Kalule , program manager, AIC, Kampala, December 11, 2002Human Rights Watch interview with Grace Ssebbanja-Namwanje, counselor for discordant couples, AIC, Kampala, January 16, 2003.

[173] Human Rights Watch interview with Josephine Kalule , program manager, AIC, December 11, 2002.

[174] Human Rights Watch interview with Grace Ssebbanja-Namwanje, counselor, AIC, January 16, 2003.

[175] Human Rights Watch interview with Robbinah Ssebbowa Ssempebwa, Action Aid, Kampala, December 16, 2002.

[176] Human Rights Watch interview with Dr. Seggane Musisi, Kampala, January 7, 2003.

[177] Human Rights Watch interview with Janet Nangobi, Iganga, January 11, 2003.

[178] Human Rights Watch interview with Masturah Tibegwya, Luwero, December 18, 2002.

[179] Real name used at her specific request.

[180] Human Rights Watch interview with Anna Isikoti, Pallisa, January 10, 2003.

[181] Human Rights Watch interview with Mabirizi Busulwa, Kampala, December 12, 2002.

[182] Human Rights Watch interview with Robina Namutebi, Kampala, December 12, 2002.

[183] Human Rights Watch interview with Dr. Seggane Musisi, Kampala, January 7, 2003.

[184] Human Rights Watch interview with Robina Namutebi, Kampala, December 12, 2002

[185] Human Rights Watch interview with Dr. Seggane Musisi, Kampala, January 7, 2003.

[186] Human Rights Watch interview with Margaret Namusisi, Iganga, January 11, 2003.

[187] Human Rights Watch interview with Magdalene Namatovu, Nakulabye, January 15, 2003.

[188] Human Rights Watch interview with Jane Akinyi, Tororo, December 17, 2002.

[189] Human Rights Watch interview with Sules Kiliesa, Tororo, December 16, 2002.

[190] Kulsum Wakabi , "Bride Price and Domestic Violence: Briefing Paper," (Kampala: the Mifumi Project/PROMPT, 2000), p. 3."Many changes have occurred in the structure of society, thereby increasing the significance of bridal wealth in these communities.Migration to towns and cities, economic decline during the Amin and Obote II era meant that families were split and increasingly impoverished.All cultural values and norms that governed bride price gave way to economic interests in most parts of Uganda. . . . Bride price has, throughout the years become increasingly commercialized and abused."

[191] Human Rights Watch interview with Masturah Tibegwya, Luwero, December 18, 2002.

[192] LAW-U, "Project Report on the Domestic Violence Study," page 81.

[193] Human Rights Watch interview with Amina Kabayondo, Mulago, January 9, 2003.

[194] Human Rights Watch interview with Dr. Kasolo, executive director, Women and Children's Crisis Centre, Kampala, December 11, 2002.

[195] Human Rights Watch interview with Ruth Mukooyo, project coordinator, FIDA Legal Aid Project, Luwero, December 18, 2002.

[196] Human Rights Watch interview with Pastor Wilberforce Owori, Tororo, December 16, 2002.

[197] MGLSD, "Third Country Status Report," p. 72.

[198] Human Rights Watch interview with Jacqueline Nakitende, Naguru , January 15, 2003.

[199] Real name used at her specific request.

[200] Human Rights Watch interview with Zebia Itata, Tororo, December 17, 2002.

[201] Human Rights Watch interview with Erasmus Ochwo, counselor, TASO, Tororo, December 17, 2002.

[202] The laws governing child custody in Uganda are found in the constitution and the Children's Statute. Article 31(4) of the constitution states, "It is the right and duty of parents to care for and bring up their children."Article 31(5) states, "Children may not be separated from their families or the persons entitled to bring them up against the will of their families or of those persons, except in accordance with the law."Section 5(1) provides that a child in Uganda has the right to live with his or her parents.

[203] Human Rights Watch interview with Rhoda Nanyonjo, Kampala, December 12, 2002.

[204] Human Rights interview with Berna Alupo, Pallisa, January 10, 2003.

[205] Human Rights Watch interview with Susan Birabwa, Kampala, December 12, 2002.

[206] Michael A. Koenig et al., "Domestic Violence in Rural Uganda: evidence from a community-based study," p. 56.

[207] Human Rights Watch interview with Rose Kyolaba, Mulago, January 9, 2003.

[208] Human Rights Watch interview with Philip Wanyama, LC1 chair, Kampala, December 12, 2002.

[209] Human Rights Watch interview with Ruth Mukooyo, project coordinator, FIDA Legal Aid Project, Luwero, December 18, 2002.

[210] Human Rights Watch interview with Martha Nanjobe, executive director, Legal Aid Project, Kampala, January 8, 2003.

[211] Human Rights Watch interview with Ruth Mukooyo, project coordinator, FIDA Legal Aid Project, Luwero, December 18, 2002.

[212] Human Rights Watch interview with Mutebi Musa Takamalirawo, Kampala, January 13, 2003.

[213] For an overview of women's property rights violations in Kenya, see Human Rights Watch, Double Standards: Women's Property Rights Violations in Kenya (New York: Human Rights Watch, 2003).

[214] Elizabeth Eilor and Renee Giovarelli , "Land Sector Analysis: Gender/Family Issues and Land Rights Component," Final Report, The Government of the Republic of Uganda, Grant No. PHRD/02/04, Rural Development Institute, February 2002, p. 21.

[215] Human Rights Watch interview with Miria Matembe, minister of ethics and integrity, Kampala, January 13, 2003.

[216] Human Rights Watch interview with Zainab Gashumba, Luwero, December 18, 2002.

[217] Human Rights Watch interview with Lydia Mpachibi, Tororo, December 17, 2002.

[219] Human Rights Watch interview with Sules Kiliesa, Tororo, December 16, 2002.

[220] Human Rights Watch interview with Jane Akinyi, Tororo, December 17, 2002.

[221] Real name used at her specific request.

[222] Human Rights Watch interview with Josephine Opio-Apiyo, Entebbe, December 13, 2002.

[223] Human Rights Watch interview with Zebia Akware, Tororo, December 16, 2002.

[224] Real name used at her specific request.

[225] Human Rights Watch interview with Sherry Simbo, Tororo, December 17, 2002.

[226] Human Rights Watch interview with Evelyn Edroma, head legal and tribunals, Uganda Human Rights Commission, Kampala, January 16, 2003.

[227] Human Rights Watch interview with Barbara Nassozi, Nakulabye, January 15, 2003.

[228] Radhika Coomaraswamy , Report of the Special Rapporteur on violence against women, its causes and consequences, February 6, 1996, U.N. Doc E/CN.4/1996/53, para. 29.

[229] The Coalition Against Gender Violence, "An Assessment of Gender Violence In Apac and Mbale Districts of Uganda," p. 19.

[230] The Coalition Against Gender Violence, "An Assessment of Gender Violence In Apac and Mbale Districts of Uganda," p. 38.

[231] Human Rights Watch interview with Hope Tumushabe, Tororo, December 17, 2002.

[232] The Directorate of Public Prosecutions exists to prosecute all criminal cases in the country on behalf of the state.

[233] Human Rights Watch interview with Maureen Owor, advocate, Owor & Co. Advocates, January 6, 2003.

[234] Human Rights Watch interview with Jackie Asiimwe-Mwesige, coordinator, UWONET, Kampala, December 14, 2002.

[235] Human Rights Watch interview with Evelyn Edroma, head legal and tribunals, and Nathan Byamukama, monitoring of treaties, Uganda Human Rights Commission, Kampala, January 16, 2003.

[236] Human Rights Watch interview with Dipak Naker, co-director Raising Voices, Kampala, December 10, 2002.

[237] Common Country Assessment, Uganda: Promise, Performance and Future Challenges, p.32.

[238] Human Rights Watch interview with Jackie Asiimwe-Mwesige, coordinator, UWONET, Kampala, December 14, 2002.

[239] Human Rights Watch interview with Jessica Saboni, police senior superintendent,Kampala, December 19, 2002.

[240] Human Rights Watch interview with Christine Mugerwa-Kasule , executive in charge of publicity, FIDA, Kampala, December 11, 2002.The "African Platform for Action," states:"(73) The absence of gender-disaggregated data based on separate records for men and women, is a source of gender blindness and gender bias against women. . . . (75) The availability of timely, valid culturally relevant data is indispensable for gender-responsive policies and programmes."

[241] Human Rights Watch interview with Apolo Nsibambi, prime minister of Uganda, Kampala, January 16, 2003.

[242] Human Rights Watch interview with Peace Kyabuleko, director, National Association of Women's Organisations, Kampala, January 17, 2003.

[243] The Children's Statute of 1996 establishes Family and Children's Courts, and outlines broad protections for children.The legislation, which draws extensively from the Convention on the Rights of the Child, includes concise provisions on the rights of Ugandan children in law and addresses the legal system's treatment of children.See Save the Children U.K., "Save the Children, Uganda Country Report," 2002, [online], http://www.savethechildren.org.uk/development/reg_pub/country_reports/Uganda_2002.pd f (retrieved April 2, 2003). There is no corresponding statute for women drawn from the Convention on the Elimination of All Forms of Discrimination against Women (CEDAW).

[244] "President Raps Bill," The New Vision, July 22, 2003.

[245] Human Rights Watch interview with Apolo Nsibambi, prime minister of Uganda, Kampala, January 16, 2003.

[246] Human Rights Watch interview with Dora Byamukama, member of parliament, and coordinator, LAW-U, Kampala, January 8, 2003.