Feasible Microbicides Remain Elusive
Microbicides 2000, a conference held March 13-16 in Alexandria, VA, signaled the rising interest in topical microbicides to prevent sexual transmission of HIV infection, other sexually transmitted diseases (STDs), pregnancy, or all three. Over 600 people, nearly half of them from outside the U.S., attended the three-day conference. A second conference, the Keystone Symposium: Novel Biological Approaches to HIV-1 Infection Based on New Insights into HIV Biology, held April 4-10 in Keystone, CO, featured additional relevant material.
The continuing absence of an HIV vaccine and the lack of access to effective anti-HIV therapy in most parts of the world has sparked increasing demands for measures that provide better protection than condoms. Condoms are widely perceived as unacceptable to many men and to women, too, because they block sensuality and intimacy as well as sperm, semen, and microbes.
Most importantly, condoms rely on the initiative of the insertive sexual partner, leaving the receptive one at a disadvantage when disagreements over condom use arise. This physical difference compounds the unequal power balance existing for women in their relations with men, such that they frequently have no recourse if their male partners refuse to wear condoms. Microbicides 2000 mostly considered vaginal microbicides that women could use with or without males' knowledge. Some consideration was also given to rectal (anal) microbicides for men's and women's use.
The conference was more an examination of the evolving state of the field rather than an expression of concrete progress. Little was presented on new trial data for candidate microbicides. Nonetheless, in an initial lecture summarizing current trials, Ronald Roddy of Family Health International counted 22 completed microbicide human trials and eight trials in progress. These trials represent about 20 products, but most of those in advanced testing involve substances that are already commercially available as spermicides. Different formulations of nonoxynol-9 (N-9) have received particular attention.
Large pharmaceutical companies are critical but missing partners in microbicide research. These companies have contributed greatly to the current array of 14 approved high-tech, high-cost anti-HIV drugs. They did provide some funding for the conference, but otherwise were virtually absent. Because of the large companies' perception that microbicides are a low-tech, low-profit area chiefly of concern to so-called Third World women, microbicide research has been left to nonprofit organizations and a few small companies. Funding largely comes from the U.S. National Institutes of Health (NIH). The Bill and Melinda Gates Foundation, the American Foundation for AIDS Research (amfAR), and the Rockefeller Foundation have made additional grants.
For the past four years, NIH funding has amounted to a modest $25 million per year. There are harbingers that microbicide research will accelerate, though: financial and logistical support from the NIH's Office of AIDS Research was critical for conducting Microbicides 2000. Also, Anthony Fauci, MD, head of the NIH's National Institute for Allergy and Infectious Diseases (NIAID), in February added another $6.5 million to this year's research pot. And in March, Representatives Nancy Pelosi (D-CA) and Connie Morella (R-MD) introduced a bill that would boost federal microbicide spending to $75 million by 2002.
The Biology of HIV Entry
Many of the basic science presentations at Microbicides 2000 stemmed from research that has some applicability to microbicide development but was not directly aimed at this topic. This lack of focus was apparent from the beginning of the conference.
Ashley Haase of the University of Minnesota gave the first scientific talk at the conference. Dr. Haase has become well known for his work visualizing HIV quantitatively inside the cells of biopsied lymph nodes and other tissue. He uses a technique called in situ hybridization that homes in on specific HIV genes and labels them with a radioactive marker. Actively reproducing HIV shows up as dark grains within cells in long-exposure photographs.
Dr. Haase described his work on the steps that the simian immunodeficiency virus (SIV), the monkey version of HIV, takes to infect a macaque monkey when it is applied vaginally. This infection process becomes detectable the third day after inoculating monkeys with the virus. At that time, the first SIV-containing cells are detectable in the lamina propria layer beneath the cervical membrane. By day 12, there is an explosion of SIV infection in lymph nodes throughout the monkeys' bodies.
Curiously, the major cell type infected in this first stage is resting CD4 T-helper cells, which produce only small amounts of HIV once they are infected. The proportion of SIV-infected, activated CD4 cells gradually rises in the following weeks. The slow rise in infected activated cells is unexpected given that activated T-helper cells are far more susceptible to SIV and HIV.
Since SIV is a model for HIV, the first steps when HIV infects humans probably closely parallels Dr. Haase's findings in monkeys. The conference attendees were left with Dr. Haase's observation that HIV is a stealthy virus before it infects activated CD4 T-helper cells in large numbers and rapidly spreads throughout the body, creating viral reservoirs in lymph nodes and among latently infected cells. Compounds that can fight HIV in the first few days of infection, before it gets out of hand, may have certain advantages over standard anti-HIV therapy.
So, what happens in the very first day of infection, when a microbicide could influence the outcome? Dendritic immune cells previously were thought to be HIV's first target in the body. Dendritic cells capture microbes on mucosal surfaces, such as the lining of the vagina, and stimulate the appropriate antigen-specific T-cells in the lymph nodes. (An antigen is any substance that produces an immune response.) Their role in early HIV infection is still under investigation.
One of the most relevant research advances pertaining to sexual transmission of HIV was unveiled not at the conference, but the previous week in Cell magazine. According to the researchers, led by immunologist Yvette van Kooyk of the University of Nijmegen in the Netherlands, HIV binds tightly to a sticky molecule known as DC-SIGN on dendritic cells' surface. DC-SIGN's normal function is to bind with a molecule on T-cells and facilitate the cell-to-cell antigen-presenting interaction.
HIV envelope protein gp 120 apparently can also bind to DC-SIGN. This binding stabilizes and protects HIV, which then becomes encased in a vesicle (capsule) within the cell. The HIV supposedly remains there in whole form while the dendritic cell inadvertently transports it to the CD4 T-helper cells in nearby lymph nodes. Once there, it tries to engage in its usual function of stimulating an immune response to the microbial antigens it has picked up. Since the HIV stays intact during this process, the dendritic cell unwittingly provides HIV with protection and transport to the susceptible CD4 T-helper cells.
Based on these findings, researchers could formulate a small molecule to block the interaction between DC-SIGN and gp120. Such a compound would have immediate application as a topical microbicide or oral prophylaxis (preventive therapy) exquisitely targeted to the first step in HIV infection of the human body. Without major industry support, however, such a DC-SIGN-blocking microbicide will be a long time in coming.
The extensive theoretical conversations at Microbicides 2000 that did revolve around inhibitors to HIV-cell binding and fusion could be irrelevant in light of the DC-SIGN report in Cell. These discussions focused on the way HIV latches onto and infects new cells via the CD4 and chemokine receptor molecules on cell membranes.
Yet none of the data concerning DC-SIGN absolutely rule out a role for CD4 and cell receptor (chemokine) blockers, and animal data do suggest that blocking this target can protect animals against HIV/SIV challenge. The initial steps in HIV transmission are hardly agreed upon. In vitro (test-tube) experiments form the basis of Dr. van Kooyk's findings and have not been confirmed in vivo (in the body). Other groups have come to different conclusions using different test techniques. At the Keystone Symposium, which took place three weeks after Microbicides 2000, Christopher Miller of the University of California at Davis presented contradictory observations on the first few days after macaque monkeys were vaginally exposed to SIV.
Following in Ashley Haase's footsteps, Dr. Miller for the first time was able to detect dendritic cells in the vaginal epithelium, or lining, that were actually infected by SIV and producing new virions (complete virus particles). By his estimate, around 10,000 cells, most of them dendritic cells, become actively infected in the first 18 hours after exposure. The envisioned CD4 and chemokine receptor blockers would definitely be valuable microbicides if this were the case.
N-9 and Safer Substitutes from Algae
For now, those attending the conference had to be satisfied with the usual collection of microbicides that are surfactants and buffers, whose general mechanisms of action do not depend on the specific steps in HIV's interaction with its target cells. These compounds are still the only ones in human testing.
Surfactants are detergents that disrupt microbial and sperm membranes by emulsification (a chemical process in which membranes are broken down). The best known such product is the over-the-counter spermicide N-9. Surfactant-containing creams and gels have the advantage of being very broad in their killing ability, but they can damage human or host cell membranes as well as those of the unwanted pathogens.
A common observation has been that N-9 causes thinning of vaginal walls. Even worse, at the Microbicides 2000 conference, researchers looking into N-9's use as a rectal microbicide showed that N-9 causes the cells lining the rectum wall to slough off in both mice and humans. The mouse experiments were part of research on protection against herpes simplex virus, the cause of "cold sore" and genital herpes. In these studies, N-9 seemed to promote death from herpes simplex even when very low amounts were applied rectally. As he spoke, Population Council researcher David Phillips displayed dramatic slides of denuded mouse rectal tissue and detached pieces of human rectal epithelial tissue that came out in post-N-9 rectal lavages (washing out of the rectal cavity).
The N-9 formulation used in these experiments was the commercial lubricant Advantage-S. Phillips warned against the popular use of N-9-containing lubricants during anal sex. Rather than protecting against viral infections, N-9 leaves a large area especially susceptible to them. The rectal walls fortunately recover within 10 to 12 hours, but by then HIV infection may have already occurred.
The Population Council is developing its own family of microbicides based on the food thickener carrageenan. Carrageenan is a seaweed (red algae) derivative that turns into a gel when mixed with water. It is a very large polysaccharide (starch) whose units contain negatively charged sulfate groups. (Other sulfated polysaccharides undergoing development as microbicides include dextrin sulfate and PRO2000.) Carrageenan was first proposed as a microbicide in the early '90s. Further testing will take at least five years and possibly longer, according to Phillips.
Carrageenan's charge causes it to stick to viral envelopes and possibly target cell membranes. By covering up critical surface molecules in this manner, carrageenan disrupts the process by which viruses latch onto and invade cells. Carrageenan may also affect some bacteria, but it has no apparent effect on sperm.
The Population Council's current lead compound, PC-515, is categorized as GRAS ("generally recognized as safe") by the FDA and is very cheap to make. It remains on vaginal walls for 6 to 18 hours, but cannot pass through them into the body due to its size. PC-515 is now undergoing Phase II studies in Thailand and South Africa.
Cyanovirin, a particularly interesting HIV-cell fusion blocker, comes from blue-green algae. It was discovered in a National Cancer Institute (NCI) screening program for natural anti-HIV agents. A protein with a complicated structure, cyanovirin binds to the sugars attached to HIV envelope protein and prevents them from binding to mucosal cell surfaces in the vagina or rectum. This mechanism would be active whether the HIV is binding to DC-SIGN or the CD4 and chemokine receptors. Cyanovirin is also active against herpes viruses.
As with carrageenan, development of cyanovirin has been exceedingly slow-paced. The chief of the NCI cyanovirin program, Michael Boyd, described it as "languishing." Apparently the NCI's production facilities, based on genetically manipulated cell cultures, have been diverted to other projects that the agency considers of higher priority. This is unfortunate: cyanovirin is of particular interest because of its relative safety. It is 10,000 times more toxic to HIV than it is to cells.
Christopher Miller, in his Keystone talk, also described a small experiment he carried out with simple white vinegar douches after vaginally inoculating female monkeys with SIV. By acidifying the vagina, the vinegar created a temporarily hostile environment that degrades SIV and, presumably, HIV too. (Earlier studies established that HIV is also very sensitive to acid.) Neither of the two monkeys douched within 15 minutes of HIV exposure became infected. Waiting 30 minutes or longer after each inoculation did not prevent Miller's monkeys from contracting HIV, especially if they were inoculated twice four hours apart.
This test is hardly conclusive, but it does highlight the broad-spectrum antimicrobial (as well as spermicidal) powers of the normally acidic vaginal environment. At Microbicides 2000, Kenneth Mayer, MD, of Brown University described a pilot study using Buffergel, a gel that works to keep the vagina at its usual acid pH of 4.0. Buffergel is under development by Baltimore-based ReProtect.
The Brown University study tested Buffergel in women with bacterial vaginosis (BV), an imbalance in the normal vaginal bacteria that can predispose women to acquire HIV and other STDs, and can also predispose pregnant women to begin labor prematurely, a risk factor for transmitting HIV to newborns. BV may make the vagina more vulnerable by neutralizing vaginal acidity and increasing the level of immune-stimulating cytokines (messenger proteins). It also frequently causes vaginal discharges and abnormal odor. Two to three days after a six-day course (seven applications) of Buffergel, seven of ten women were negative for bacterial vaginosis. One month later, four were still negative and seven had no discharge. BufferGel has been found to be safe and well tolerated in studies conducted in Rhode Island, Thailand, India, Malawi, and Zimbabwe.
Doing Nature One Better
Bacterial vaginosis does its damage by eliminating the lactobacillus bacteria in the vagina. These bacteria are largely responsible for the acidic environment, and many strains protect further by producing the antimicrobial oxidizing agent hydrogen peroxide. Hortense Faye-Ketté, in a study of 1,272 women in Abidjan, Ivory Coast, was able to correlate vaginitis with lack of lactobacilli, the hydrogen peroxide-producing strains in particular. None of the women with vaginal discharges had such strains, whereas 21% of the healthy women did. (Recently, new sensitive assays have found that Lactobacillus acidophilus, the species used to make yogurt, is not one of the normal vaginal strains.)
Lactobacilli accomplish their protective acidification by breaking down the glycogen, a form of carbohydrate, that the vagina produces when stimulated by estrogen (a female sex hormone). Estrogen also has a more direct effect: Preston Marx of the Aaron Diamond AIDS Research Center in New York pointed out that estrogen protects against HIV by greatly thickening the vaginal wall. Topical estrogen therefore might have a valuable prophylactic role, especially in postmenopausal women and those on progesterone-based birth control pills. Marx tested his theory on monkeys given estrogen implants after their ovaries were removed. Such monkeys were protected from SIV introduced vaginally but not intravenously.
It would be easy enough to introduce the right lactobacilli, but Gianni Pozzi, of the University of Siena, Italy, wants to go a step further. He proposes genetically engineering lactobacilli so that they produce cyanovirin in addition to their other beneficial qualities. Dr. Pozzi has already tried this technique on Streptococcus gordonii, a common, harmless oral bacterium that can also colonize the vagina.
A parallel study by Dr. Pozzi involved S. gordonii engineered to produce an anti-yeast antibody. The bacteria proved highly effective in controlling vaginal candidiasis in rats. One version was 100% protective for at least four weeks after treatment.
Topical monoclonal antibodies (antibodies derived from a single clone of cells) that bind to the HIV envelope protein would be a highly effective measure that could prevent HIV infection for several days, according to Richard Cone, of Johns Hopkins University and ReProtect, at Microbicides 2000. These antibodies would mimic natural acquired immune protection without requiring exposure to disease-causing cells or viruses. They would target a particular protein on a microbe, causing it to be trapped on mucosal surfaces and unable to adhere to human cells. One initial experiment in monkeys using an SIV-HIV hybrid observed a promising degree of protection even with only modestly active antibodies.
Dr. Cone noted that anti-sperm antibodies exist, too. Combinations of different antibodies could attack a broad range of STDs and sperm, as desired. Ideally, a daily intravaginal pill or long-lasting vaginal ring containing a mixture of antibodies could provide a simple means of protection that would have no disturbing effect on sexual sensation.
A major problem is that monoclonal antibodies are inordinately expensive. This hurdle has led Epicyte Pharmaceuticals of San Diego to suggest producing them cheaply in transgenic (genetically modified) rice plants. The company has already created such plants to produce antibodies to herpes simplex.
In a world already awash with protests over genetically altered food, use of such techniques to produce microbicides may well provoke further controversy. A cyanovirin-producing lactobacillus could spread from woman to woman on its own (i.e., vertical transmission from mother to daughter, or horizontal transmission, among women living in the some residence and, for example, sharing a bathroom) -- a chilling prospect. And from a commercial standpoint, how can you sell a self-perpetuating product?
On the other hand, these altered organisms are not food but would be used in one organ for a specific medical purpose. The new genes they contain would have no known function in the wider environment. Their expression in plants would not create pesticide-resistant insects or superweeds, nor would it create a known toxic threat to people. These are the common objections to other types of genetically modified agricultural plants. And the antibodies, at least, would require further processing before use (i.e., extraction, purification, and concentration) so that they would always be a salable commodity.
Drug resistance on the part of the targeted microbes would remain an issue. This is the case with any medication with a microbe-specific target of action rather than general activity, such as acidity modification.
Ameliorating Environmental Risk Factors
The risk of HIV transmission varies greatly from community to community across the globe. The background environmental factors that affect transmission are not yet well elucidated. Determining those factors could aid considerably in HIV prevention, with or without a specifically anti-HIV microbicide.
At the 7th Conference on Retroviruses and Opportunistic Infections (CROI) held in San Francisco this past winter, Anne Buvé described a study she conducted to see what determined the varying HIV rates in different African cities. This massive study included two West African towns in which less than 5% of pregnant women have HIV and two in East Africa where more than 25% are infected. One thousand persons from the general population plus 300 sex workers were interviewed and tested in each city.
The study found that the main factors associated with high HIV rates are the level of other STDs, particularly genital herpes in men and trichomoniasis in women, and lower frequency of male circumcision (the men in the two West African towns were nearly all circumcised). Except for women's age at first intercourse, which was younger in East Africa, there were no distinguishing variations in sexual behavior among the four cities. Number of lifetime sexual partners and contact with prostitutes were both similar for all four cities.
These observations were confirmed at Microbicides 2000 by Thomas Quinn, who added another factor to the interplay that affects the risk for transmission: low viral load in the person with HIV. In a Johns Hopkins-Makerere University study that was published two weeks later in the New England Journal of Medicine, researchers followed 415 serodiscordant heterosexual couples in rural Uganda for up to 30 months. The male partner was HIV-1 positive and the female partner was HIV-1 negative in 228 of the couples, and the reverse was true for 187 couples. No one became infected among the 50 circumcised HIV negative men with HIV positive wives. By comparison, 40 of the 137 uncircumcised HIV negative men seroconverted. When an HIV positive man was circumcised, the risk of HIV transmission to the woman decreased 60%.
In this study population, condom use was very low and antiretroviral therapy nonexistent. The second major finding was that HIV sexual transmission risk is highly dependent on the infected person's viral load. This correlation has been widely debated. The Ugandan study reported that a 1-log (10-fold) increase in viral load raised the transmission risk 2.45 times. No one with a viral load below 1,500 copies/mL transmitted his or her HIV. Viral load turned out to be a much stronger predictor of transmission than the symptoms of STDs. STDs were specifically diagnosed only at the start and the end of the study, however.
Viral Load in the Blood and Genital Tract
Since anti-HIV treatment is generally unavailable in Uganda, the viral load results will mainly benefit the citizens of other, richer countries. Whether circumcision receives recognition as a public health measure is questionable, though not unimaginable. In addition, the Ugandan data do not necessarily predict transmission risk on an individual basis. Viral load in blood plasma -- which the study measured -- and in genital secretions do not absolutely correlate.
At Microbicides 2000, Robert Coombs, MD, of the University of Washington presented examples from his cohort of women with treatment-suppressed HIV in their blood but viral loads in their endocervical fluid as high as 15,000 copies/mL. Endocervical viral load in general did not match well with blood plasma viral load in Dr. Coombs's study population of 550 women, and genital viral load variations were greater than the variations in plasma. The fluid within the cervix amounts to only about two teaspoons, but the presence of replicating HIV there occurs at a critical place as far as sexual transmission is concerned.
A similar situation exists in semen, according to Dr. Coombs's earlier work. A Microbicides 2000 presentation by Christine Rouzioux of the Hôpital Neckar-Enfants Malades in Paris also described finding discrepancies between men's plasma and seminal viral loads, whether the men were treated or not. Dr. Rouzioux also stressed the importance of persistent HIV DNA within infected seminal cells, which includes lymphocytes. Cells containing HIV DNA frequently persevere in semen despite successful antiretroviral therapy and are a possible a source of transmission.
Dr. Coombs thinks the discordance in genital tract and blood plasma viral load arises because genital lymph tissue operates as a separate compartment to combat infections restricted to that region. The localized immune excitation by means of inflammatory cytokines also stimulates whatever HIV is present in the white blood cells, leading to the growth of HIV even in the presence of anti-HIV therapy, i.e., a disruption in the balance between HIV and whatever antiretroviral drugs are present. The result is a viral flare-up that exposes sexual partners to HIV in addition to permitting viral evolution that may lead to drug resistance.
Among the pro-inflammatory cytokines, IL-1b was particularly correlated with detectable genital HIV in an examination of 34 women performed by Julie Villaneuva of the Centers for Disease Control (CDC). A higher vaginal white blood cell population was another associated factor. Both bacterial vaginosis and N-9 increase vaginal IL-1b and white blood cell levels.
The female cervix's internal location and complex structure, covered by a thin layer of tissue known as transitional epithelium, make it a frequent initial target of sexually transmitted microbes (infections). Also, uterine contractions during sex draw semen into the cervix. Young women, especially teenaged women, are even more vulnerable to HIV infection than older women; the cell type covering the cervix changes as girls mature into full adulthood to become more impervious to microbes and other pathogens.
Thomas Moench of ReProtect and Nancy Padian, PhD, of the University of California at San Francisco argued in a Microbicides 2000 poster presentation that a diaphragm or similar barrier would provide valuable additional protection. Analogous to its role in contraception, a microbicide-laden diaphragm would serve as a trap for pathogens on their way to the cervix.
Ensuring the proper distribution of microbicide and blockage of semen is even more problematic in the rectum. The rectum is of larger volume than the vagina and completely open internally. It also has a different, nonacidic microbial environment.
A diaphragm-like device would be unworkable there. At the very least, a comparatively large volume of microbicide would be necessary for rectal protection. Although several studies at Microbicides 2000 documented the distribution of microbicide within the vagina (involving MRI scans), nothing appeared on how microbicides distribute themselves in the rectum or how that distribution changes during sex.
Another issue holding up progress is the continuing debate over ethical trial design. In the Johns Hopkins-Makerere University study, persons found to have HIV were advised to tell their partners, but no effort was made to ensure that they did so. Increasing the risk of transmission was the lack of condom use or antiviral treatment. Although there was considerable discussion about proper trial design at Microbicides 2000, no objection was made to the conditions in this trial. Protest arose only after the article appeared in the New England Journal of Medicine.
The lack of treatment or even counseling in this study meant that international standards of care were not maintained. As Marcia Angell, acting editor of the New England Journal of Medicine, observed in an editorial, such a study would be impermissible in an industrialized country. Ethically speaking, research subjects are supposed to receive standard-of-care treatment to protect them from obvious harm. This makes good scientific sense, too: a trial is only worthwhile if it shows whether an experimental intervention is better than standard treatment, not whether it is better than nothing at all. That is, is it fair or ethical to foist a marginally effective agent on Third World communities just because they may be poor? The point is to find the best scientifically possible treatment and to provide such treatment to all communities, regardless of economic status.
The continuing debate over this study should serve as a warning about the design of microbicide trials in the future: wherever they live, trial participants will have to be extensively counseled about safer sex, warned of known exposures to HIV, and advised of other methods to avoid infection. Of course, if you do all that, it becomes hard to tell whether the microbicide works. Trials will have to enroll more people and/or last longer.
While the clinical trials process plods slowly along, much of the basic science has yet to be settled, and basic microbial design issues remain unclear. It seems that it will take a long time to arrive at a marketable microbicide. Still, the idea has growing appeal and could be embodied in a soft-tech approach feasible throughout the world. Many possible agents are already available. Toxicities and cost need not present much of an obstacle even for a microbicide with broad-spectrum activity. The technological hurdles do not appear to be that difficult -- given sufficient political will.
Dave Gilden is Director of Treatment Information Services at amfAR.
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Briggs, K. and others. An anti-HSV antibody produced in transgenic rice plants prevents vaginal HSV-2 infection in mice. Microbicides 2000. Abstract A10.
Buvé, A. Factors determining differences in rate of spread of HIV in Sub-Saharan Africa: results from a population based survey in four African cities. 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30-February 2, 2000. Oral presentation S28.
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Faye-Ketté, H. and others. Hydrogen peroxide-producing lactobacilli in women with and without vaginal discharge: evidence for a role in vaginitis prevalence. Microbicides 2000. Abstract A20.
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Moench, T. and others. Disease prevention by protecting the cervix. Microbicides 2000. Abstract B17.
Phillips, D.M. and others. N-9 causes exfoliation of sheets of rectal epithelium. Microbicides 2000. Abstract B19.
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Quinn, T. Viral load and treatment in Uganda. Microbicides 2000. Oral presentation.
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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.