24 NOVEMBER 2010, VOLUME 11, ISSUE 44

Background Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition.

Methods We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections.

Results The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57).

Conclusions Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect.

See related editorial also published in the New England Journal of Medicine, "Oral preexposure prophylaxis for HIV -- another arrow in the quiver?".

This update contains information about the groundbreaking news from the iPrEx trial, which showed that daily TDF/FTC (brand name Truvada) as pre-exposure prophylaxis (PrEP) reduced the risk of HIV in HIV-negative gay men, transgender women and other men who have sex with men (MSM).

The iPrEx trial found that participants who received TDF/FTC in addition to a standard prevention package had an overall 43.8% reduced risk of HIV compared to participants who received the placebo along with the prevention package. This is the first evidence that oral PrEP can reduce risk of HIV infection. iPrEx is also the first trial showing effectiveness of a new biomedical prevention tool in gay men and other MSM. The iPrEx trial enrolled 2,499 participants across 11 sites in six countries -- Brazil, Ecuador, Peru, South Africa, Thailand and the United States. It is the first PrEP effectiveness trial to report results. This trial was one of a suite of PrEP trials currently ongoing in a range of populations around the world.

• 3 big developments make AIDS outlook more hopeful
  Marilynn Marchione, Associated Press
• Daily pill lowers H.I.V. infection risk, study finds
  Donald G. Mcneil Jr., The New York Times
• MSM study shows great HIV prevention promise
  Lungi Langa, Health-e News
• PrEP cuts HIV risk by 44%
  Liz Highleyman, Bay Area Reporter
• Anti-HIV pill protects against AIDS
  Jon Cohen, Science
• Gilead pill helps prevent HIV in 'breakthrough' study
  Simeon Bennett and Rob Waters, Bloomberg
• Pill shows a drop of up to 70% in HIV infection risk
  Thomas H. Maugh II, Los Angeles Times
• Pill cuts HIV infection risk significantly, for a price
  April Fulton, National Public Radio
• Anti-HIV drugs prevent HIV infection, trial shows -- if you take them
  Gus Cairns, Aidsmap
• HIV drugs taken preemptively cut rate of infection almost in half
  Katherine Harmon, Scientific American
• Giving drugs to prevent HIV lowered infection rate
  Elizabeth Cooney, Boston Globe
• Preexposure chemoprophylaxis reduces HIV infections in gay and bisexual men
  Robert Lowes, Medscape Today
• Study: AIDS pill helps gay men avoid HIV infection
  Associated Press

South Africa could cut the number of new HIV infections to below 200,000 a year by 2020, more than half the current level, with the right policies, but reaching the goal will be costly, a report on Friday said. South Africa has the most infected people of any country in the world with 5.7 million with HIV, according to data from the U.N. programme on HIV/AIDS (UNAIDS). Around 18 percent of South Africans aged between 15 and 49 are infected. "This situation poses huge financial dangers and risks for the country, particularly at a time when South Africa is feeling the negative effects of the global economic recession," the report said. The report recommends drawing up and funding more effective plans for prevention, treatment and halting the transmission of the virus from infected parents to their children.

Natural killer cells are major weapons in the body's immune system. They keep the body healthy by knocking off tumors and cells infected with viruses, bombarding them with tiny lethal pellets. But natural killer cells are powerless against HIV, a fact that has bedeviled science for over 20 years. Now, researchers at Rush University Medical Center have discovered the reason why. The study, posted online this week in the prestigious peer-reviewed journal Cell Host & Microbe, marks the "beginning of a fascinating story that will shed new light on an important but still poorly understood aspect of the interaction of HIV with natural killer cells," according to an editorial in the journal. "With this information, we now have a major new target for drug therapies that could potentially stop HIV and allow the body's natural killer cells to do what they are designed to do -- protect the body from this lethal virus," said Edward Barker, PhD, associate professor of immunology and microbiology at Rush University and lead author of the study.

HIV, like any virus, is bent on producing progeny. It infects a cell, replicates itself over and over, and spreads throughout the body by using its "accessory" proteins to both take over the machinery of the cells it inhabits and thwart the arsenal of immunological cells that might destroy it. Oddly, some of these proteins work at cross purposes. One, the Vpr protein, initiates what is called DNA damage repair, stopping the host cell in its tracks so that the virus can take over. But that action also sends a message to the cell surface that something is amiss. A ligand, called ULBP, is sent to the surface of the cell, which the prowling natural killer cells recognize and latch onto -- the initial steps just before moving in for a kill. Meanwhile, another protein produced by HIV prevents the cytotoxic T cells of the immune system from homing in on the HIV-infected cell and obliterating it. But this same protein also provokes the natural killer cells into action by shutting down an inhibitory mechanism that would hold the killer cells back.

To read the study abstract, see "Degranulation of natural killer cells following interaction with HIV-1-infected cells is hindered by downmodulation of NTB-A by Vpu" in the "Published Research" section of this NewsDigest.

Bionor Pharma ASA almost quadrupled in value in Oslo trading, gaining more than $45 million, after the drugmaker said its experimental HIV vaccine unexpectedly reduced virus levels. Bionor shares climbed as much as 285 percent after the Oslo-based company today said it will resume development of the treatment. The drugmaker last month canceled the Vacc-4x program after an early study showed patients taking the vaccine were just as likely as those receiving a placebo to have to resume antiretroviral therapy. The study was designed to see if the vaccine helped patients to stay off the therapy, which typically consists of a combination of three or more drugs. Further analysis of the study data showed the vaccine triggered an "unexpected" and statistically significant drop in levels of the virus, which causes AIDS, Bionor said today. Virus levels in vaccinated patients didn't return to pre-therapy levels, which normally happens, the company said.

Men who have unprotected sex with other men, commonly known as "barebacking," represent a challenge to HIV prevention activities. A poster presented here at the American Public Health Association 138th Annual Meeting showed that these men believe their risk to be low, when in fact it is high. The study examined 16 Web sites that cater to men who have sex with men. Either they were geared specifically toward unprotected sex or they were sites with a specific opportunity to list "whether you are looking for safe sex only, unprotected sex only, or don't care," explained principal investigator Hugh Klein, PhD, from the Prevention Sciences Research Center at Morgan State University in Baltimore, Maryland. The "don't care" category had to include some explicit statement in the ad to meet the barebacking inclusion criteria.

The researchers used a strict algorithm to screen Web pages to ensure adequate representation by age, race, and geographic location (rural, urban, suburban), and it sampled at different times of the day. Coauthor David Tilley, a doctoral student at the University of South Florida College of Public Health in Tampa, said that interviewers were instructed to randomize by the first letter or number of the profile within their assigned ethnic group for that day, which resulted in a 26% minority sample. It was difficult to compute response rates because some sites allowed the researcher to see if the person was online and/or if they had opened the email asking them to participate in the survey, whereas other sites did not offer that feature and email was deleted after a fixed period of time. Dr. Klein said: "My best guess is 10%, but it is exceedingly difficult to know."

As he reflects on the more than two-decade journey of the Entebbe-based Uganda Virus Research Institute in HIV/Aids research, Executive Director Edward Katongole-Mbidde beams with restrained satisfaction.

In that time, UVRI, which began HIV/Aids research around 1987, has registered a number of significant milestones. In a series of collaborative research initiatives with partners from different countries in Europe and the Americas, UVRI has tracked the spread of HIV/Aids for more than 20 years, carried out the first HIV vaccine trial in Africa, and undertook a trial which showed that the most common disease of the central nervous system in HIV-infected people in Africa could be prevented with a pill. Propped up by support from the Medical Research Council (MRC) of Britain, UVRI also undertook a trial to develop specialised anti-retroviral therapy for Africa, which helped save money.

In addition, UVRI was the first to isolate more than 20 new arboviruses, including West Nile Virus, Bwamba Fever, Semliki Forest Virus, Orungo, Kadam, and O'nyong'nyong. While UVRI has grown to become the centre for virus research in the country and one of the most renowned on the continent, Dr Katongole-Mbidde says its beginnings were quite modest.

On World Aids Day we pay tribute to the millions who are infected and affected by HIV/Aids worldwide. We continue to spread the word that in spite of much success, too many lives are still being devastated by this deadly disease. Our task looms large, but our message is simple: we have a shared responsibility as governments and individuals to build on the success achieved by making smart investments and decisions that will ultimately save more lives. And there is much success to build on. Globally, more than five million people in low- and middle-income countries are on HIV treatment, and the American people support more than half of these individuals through the President's Emergency Plan for Aids Relief (Pepfar). In addition, Pepfar programmes have helped more than 340000 babies to be born free of HIV. Millions more have benefited from HIV prevention and care programmes.

In South Africa, our partnership with the government is saving thousands of lives. Pepfar support from 2004 to 2009 was more than R15-billion, and is helping about 650000 people receive antiretroviral treatment. More than 2.1 million people have received HIV-related care through this programme, and nearly 500000 orphans and vulnerable children have received support services. In addition, the embassy's community grants programme helps rural and township community-run projects by strengthening service delivery in communities affected by HIV/Aids, including orphans and vulnerable children, as well as palliative and home healthcare. The programme provided more than R13-million in funding to rural community NGOs in 2009 alone.

The findings of several studies on HIV treatment and prevention will soon be revealed, shedding new light on a disease that, while much more effectively controlled than ever before, continues to be transmitted in Ontario, HIV/AIDS professionals heard Monday during the Regional HIV and AIDS Symposium in Guelph. B.J. Caldwell, HIV/STI prevention/outreach educator with the AIDS Committee of Guelph, told about 50 symposium participants that much will be learned in the coming months about the efficacy of new approaches to HIV prevention, including a so-called preexposure prophylaxis that is currently being tested. The study will help determine whether a daily dose of anti-HIV medications, taken by an HIV-negative person prior to potential exposure, can offer a new level of defence against the virus. Similar approaches have been used to protect against diseases like malaria, Caldwell said.

The spread of HIV depends on how much of the virus -- the viral load -- is coursing through a person's veins, Caldwell explained. The initial stage of infection -- before the immune system kicks in to combat it -- is when the load is at its most concentrated and most infectious, even though symptoms may be non-existent. Current treatments are effective at greatly reducing the viral load to undetectable levels, but new studies are ongoing to better determine when antiretroviral treatment should begin. Caldwell said "treatment as prevention" measures appear to work at preventing the spread of the virus. There is a trend, he said, toward starting treatment earlier to prevent the spread in those initial stages of infection.

When researchers returned to Zimbabwe several months after the end of a trial involving condom and diaphragm use, they were disappointed to find that condom use - which had risen to 86 percent during the trial - had reduced significantly. "What happens after trials has always remained very much a mystery, and today, with biomedical prevention that has proved to be partly efficacious, such as the microbicide gel from the CAPRISA trial [which found that a vaginal gel containing tenofovir, an antiretroviral (ARV) drug, was 39 percent effective at reducing women's risk of contracting HIV during sex], it would be interesting to see what happens after the trial," Ariane van der Straten, lead author of a recent study on the issue, told IRIN/PlusNews. "We were disappointed to see that all the effort and intense counselling provided to participants didn't seem to have a long-lasting effect - in effect, condom use went back to enrolment levels."

The Methods for Improving Reproductive Health in Africa (MIRA) trial, conducted between 2003 and 2006 in South Africa and Zimbabwe, evaluated the effectiveness of the diaphragm in the prevention of HIV and other sexually transmitted infections (STIs). It involved more than 5,000 women randomized into two arms - one group received a diaphragm, lubricant and male condoms, while the other received only male condoms; participants received intensive HIV counselling as well as STI treatment. The trial found that the diaphragm and lubricant did not provide extra protection compared to condoms and treatment of STIs. The follow-up study involved 801 women who were assessed 2-20 months after the end of the MIRA trial. During the MIRA trial, condom use rose to about 86 percent, but dropped to about 67 percent during post-trial visits.

As the death toll from the cholera epidemic sweeping through Haiti surpasses 1,000, with more than 19,000 confirmed cases, health officials say people living with HIV are especially vulnerable. Only about 25 percent of people infected with cholera develop symptoms - mainly watery diarrhoea and vomiting - but people already weakened by illness, malnutrition or pregnancy are particularly at risk. "[People living with HIV] are very much at risk because they already have a weakened immune system," explained Hanz Legagneur, director of the Ministry of Public Health in the country's West Department.

Cholera can be easily treated with oral rehydration salts that replenish the body's water and electrolytes, but can be deadly for people who fall ill quickly and lose too much water before obtaining assistance. People living with HIV are often too poor to pay for transport to health facilities, which can prove deadly when time is short. "Anyone can die within four hours without treatment or oral rehydration salts; [for] someone infected with HIV it will be even less - it can be two or three hours," said Reginald Dupont of SeroVIE, an NGO for lesbian, gay, bisexual and transgendered Haitians living with HIV.

Over the past several years, the number of people needing treatment for HIV/AIDS has risen, but so has the amount of funding for the treatment and prevention of the disease. The United States has been at the forefront of that funding, but with the new emphasis in Washington on reducing government spending that may be about to change. Even though the U.S. lags behind many European countries in terms of global health contributions as a proportion of GDP, it remains the single largest funder of health assistance to developing countries.

This is why the new U.S. Congress that was elected earlier this month and will take office in January is somewhat concerning to global health advocates. Republicans will take control of the U.S. House of Representatives and have made it clear that reducing government spending in order to close the government's budget deficit will be a top priority. This platform was laid out in September, when House Republicans made what they called a "Pledge to America". Among their proposals was reducing so-called non-security- related spending for fiscal year 2011 to fiscal year 2008 levels, meaning this spending would be 21.7 percent below what President Barack Obama has requested. And the preliminary recommendations from a panel commissioned by Obama to look at ways of reducing the federal budget deficit includes cuts to a foreign aid budget many NGOs say is already too small.

It is far from clear how many of these proposals will succeed in getting implemented, nor how spending cuts would be distributed across programmes, but it is widely expected that there would be steep cuts to HIV/AIDS programmes and research -- as well as other areas of global health and foreign assistance funding. Most frustrating for NGOs is that those cuts would come just U.S.-funded AIDS work is seeing strong successes.

When it comes to understanding what drives HIV infections among young people in southern Africa, the epicentre of the global AIDS pandemic, why not ask young people themselves? A five-country study by the Southern African AIDS Trust (SAT) in partnership with the Health Economics and AIDS Research Division (HEARD) at the University of KwaZulu-Natal did just that, and the picture that has emerged is more complex than many prevention programmes targeting youth have allowed for. "Life is complicated so our prevention interventions need to find ways to engage with these complexities," Jo Vearey, who is coordinating the regional research project, told delegates at the HIV/AIDS in the Workplace Research Conference in Johannesburg on 10 November.

While a growing number of children who were born with HIV are surviving into adolescence, the majority of young people acquire the virus through sex, and young women are at particular risk. The overall prevalence of HIV among youth (aged 15-24) in southern Africa is about 1 percent in males and 3 percent in females, but in some countries it is much higher. In general, efforts to reduce HIV infections in young people in the region have not succeeded, said Vearey. "We need to acknowledge that, take a deep breath and move forward."

Researchers have been stymied for years over the fact that people infected with the AIDS virus do indeed produce antibodies in response to the pathogen -- antibodies that turn out to be ineffective in blocking infection. Now, scientists at Duke University Medical Center can explain why: Some of the earliest and most abundant antibodies available to fight HIV can't actually "see" the virus until after it's already invaded a healthy cell. The scientists based their conclusion on the results of a series of crystallography and biochemical experiments that revealed the specific molecular structures different types of antibodies need to have in place in order for them to mount an effective defense. Previous research had shown that two of the most robust antibodies against HIV -antibodies called 2F5 and 4E10 -- target a specific part of the outer coating of the virus called the MPER region of gp41. The antibodies, which operate in a lock and key relationship, are able to latch on to the virus as it reveals this vulnerable part of its structure, referred to as an "Achilles heel" of the AIDS virus.

"What our studies revealed, however, is that the virus actually creates two versions of this 'Achilles heel,' says Barton Haynes, MD, director of the Duke Human Vaccine Institute (DHVI) and the senior author of the study appearing online in Nature Structural & Molecular Biology. "One version is for these rarer, broadly-neutralizing antibodies, and the other is for the more abundant, first-responding antibodies that won't be able to do much good because the Achilles heel isn't detectable to them until the virus has already gained entry."

To read the study abstract, see "Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane-proximal external region" in the "Published Research" section of this NewsDigest.

An estimated 33.3 million people worldwide have the HIV virus that causes AIDS, but the global health community is starting to slow down and even turn the epidemic around, a United Nations report said on Tuesday. The total number of HIV-infected people in 2009 was down slightly from the previous year's 33.4 million and at least 56 countries have either stabilized or achieved significant declines in rates of new HIV infections.

Yet while more than 5 million of those who need life-saving AIDS drugs are getting them, around two-thirds of the 15 million people in poorer countries who need them cannot get them. Marginalized groups like drug users and sex workers are far less likely to get help than others, according to the 2010 global update by the Joint U.N. Programme on HIV/AIDS (UNAIDS). "For the first time, we can say that we are breaking the trajectory of the AIDS epidemic. We have halted and begun to reverse the epidemic. Fewer people are becoming infected with HIV and fewer people are dying from AIDS," UNAIDS Executive Director Michel Sidibe said as the report was released.

To read the UNAIDS report, click here.

Fewer people are being infected with the virus that causes AIDS than at the epidemic's peak, but progress against the disease is still halting and fragile, the United Nations' AIDS-fighting agency reported Tuesday. In its new report on the epidemic, Unaids said 2.6 million people became newly infected with H.I.V., the virus that causes AIDS, in 2009 -- almost 20 percent fewer than in the late 1990s.

But progress is spotty. About 25 countries are doing better at prevention, including several in southern Africa with sky-high AIDS rates. South Africa, which has the world's worst epidemic, has benefited from the changeover from the presidency of Thabo Mbeki, which was hostile to the distribution of AIDS drugs, to that of Jacob Zuma, who has publicly taken an AIDS test and urged citizens to do the same. Still, it faces an estimated 350,000 to 500,000 new infections annually. In one area, progress has been heartening: giving mothers drugs to prevent the infection of their babies at birth or through breastfeeding. "We've had a 50 percent reduction of infections among young people in South Africa, which is a huge reservoir," Michel Sidibe, executive director of Unaids, said in an interview in Manhattan last week.

Natural killer (NK) cell degranulation in response to virus-infected cells is triggered by interactions between invariant NK cell surface receptors and their ligands on target cells. Although HIV-1 Vpr induces expression of ligands for NK cell activation receptor, NKG2D, on infected cells, this is not sufficient to promote lytic granule release. We show that triggering the NK cell coactivation receptor NK-T- and -B cell antigen (NTB-A) alongside NKG2D promotes NK cell degranulation. Normally, NK cell surface NTB-A binds to NTB-A on CD4+ T cells. However, HIV-1 Vpu downmodulates NTB-A on infected T cells. Vpu associates with NTB-A through its transmembrane region without promoting NTB-A degradation. Cells infected with HIV-1 Vpu mutant elicited at least 50% more NK cells to degranulate than wild-type virus. Moreover, NK cells have a higher capacity to lyse HIV-infected cells with a mutant Vpu. Thus, Vpu downmodulation of NTB-A protects the infected cell from lysis by NK cells.

See related article in the "Media Coverage" section of this NewsDigest: "Discovery in how HIV thwarts the body's natural defense opens up new target for drug therapies".

Background We conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol. The HIV sequences were derived from circulating recombinant form CRF01_AE, which predominates in Thailand. The objective was to evaluate safety and immunogenicity of MVA-CMDR in human volunteers in the US and Thailand.

Methodology/Principal Findings MVA-CMDR or placebo was administered intra-muscularly (IM; 10⁷ or 10⁸ pfu) or intradermally (ID; 10⁶ or 10⁷ pfu) at months 0, 1 and 3, to 48 healthy volunteers at low risk for HIV-1 infection. Twelve volunteers in each dosage group were randomized to receive MVA-CMDR or placebo (10:2). Volunteers were actively monitored for local and systemic reactogenicity and adverse events post vaccination. Cellular immunogenicity was assessed by a validated IFN-gamma Elispot assay, an intracellular cytokine staining assay, lymphocyte proliferation and a 51Cr-release assay. Humoral immunogenicity was assessed by ADCC for gp120 and binding antibody ELISAs for gp120 and p24. MVA-CMDR was safe and well tolerated with no vaccine related serious adverse events. Cell-mediated immune responses were: (i) moderate in magnitude (median IFN-gamma Elispot of 78 SFC/106 PBMC at 10⁸ pfu IM), but high in response rate (70% 51Cr-release positive; 90% Elispot positive; 100% ICS positive, at 10⁸ pfu IM); (ii) predominantly HIV Env-specific CD4+ T cells, with a high proliferative capacity and durable for at least 6 months (100% LPA response rate by the IM route); (iv) dose- and route-dependent with 10⁸ pfu IM being the most immunogenic treatment. Binding antibodies against gp120 and p24 were detectable in all vaccination groups with ADCC capacity detectable at the highest dose (40% positive at 10⁸ pfu IM).

Conclusions/Significance MVA-CMDR delivered both intramuscularly and intradermally was safe, well-tolerated and elicited durable cell-mediated and humoral immune responses.

Background Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2) vaginal susceptibility models. In addition, "inactive ingredients" (or excipients) used in topical formulations to deliver active molecules might also cause epithelial toxicities that increase viral susceptibility. However, excipients have not previously been tested in susceptibility models.

Methods Excipients commonly used in topical products were formulated in a non-toxic vehicle (the "HEC universal placebo"), or other formulations as specified. Twelve hours after exposure to the excipient or a control treatment, mice were challenged with a vaginal dose of HSV-2, and three days later were assessed for infection by vaginal lavage culture to assess susceptibility.

Results Significantly increased transmission of HSV-2 was observed after a single exposure to 5% glycerol monolaurate (GML) formulated in the extremely hypertonic vehicle K-Y(R) Warming Jelly, with this vehicle alone, with its neat humectant/solvent components (propylene glycol and PEG-8), and with 5% GML as a colloidal suspension in phosphate buffered saline. For excipients formulated in the HEC vehicle, a trend toward increased HSV-2 transmission was seen after 0.1% disodium EDTA, but not after 0.0186% disodium EDTA. Increased susceptibility was not observed following exposure to 10% glycerin, 10% propylene glycol, 0.18%, methylparaben plus 0.02% propylparaben, or 1% benzyl alcohol.

Conclusions As reported with other surfactants, the surfactant/emulsifier GML markedly increased susceptibility to HSV-2. A hyperosmotic vehicle gel and its neat individual hyperosmotic excipients also markedly increased susceptibility.

Six randomized clinical trials have been implemented to examine the efficacy of tenofovir disoproxil fumarate (TDF) and/or TDF/emtricitabine (TDF/FTC) as pre-exposure prophylaxis for HIV-1 infection (PrEP). Although largely complementary, the six trials have many similar features. As the earliest results become available, an urgent question may arise regarding whether changes should be made in the conduct of the other trials. To consider this in advance, a Consultation on the Implications of HIV Pre-Exposure Prophylaxis (PrEP) Trials Results sponsored by the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation (BMGF), was held on January 29, 2010, at the Natcher Conference Center, NIH, Bethesda, MD. Participants included basic scientists, clinical researchers (including investigators performing the current PrEP trials), and representatives from the U.S. Food and Drug Administration (FDA) and the agencies sponsoring the trials: the U.S. Centers for Disease Control and Prevention (CDC), the U.S. Agency for International Development (USAID), the BMGF, and the U.S. NIH. We report here a summary of the presentations and highlights of salient discussion topics from this workshop.

The microbiota of the human vagina can affect the health of women, their fetuses, and newborns. Bacterial vaginosis (BV) is the most prevalent form of vaginal infection in women of reproductive age, affecting 8% to 23%, and is the most common etiology of vaginal symptoms prompting women to seek medical care. While traditional cultivation has identified numerous BV-associated bacteria involved in these processes, recent advances in molecular biology have facilitated the detection and identification of bacteria without cultivation, some of which have not previously been described or well characterized. A more complete understanding of vaginal microbial populations resulting from the adoption of molecular tools may lead to better strategies to maintain healthy vaginal microbial communities -- thus enhancing women's health -- and will create opportunities to explore the role of novel bacteria in reproductive tract diseases. On November 19-20, 2008, the NIH convened a workshop of experts in the field of research and clinical practice related to BV in order to discuss how these new advances should be interpreted and applied to research in progress and collaborations between relevant disciplines. This paper summarizes the presentations of this workshop and outlines general recommendations arising from the related discussions. Future studies of BV and its associated adverse outcomes should determine if specific combinations of organisms are more pathogenic than others, and causally associated with different adverse events. Moreover, determination of causality will depend not only on more precise categorization of the vaginal microbiota, but also on variations in the host environment that may be associated with changes in bacterial communities over time. In this report, we offer suggestions and recommendations that we hope will facilitate conduct of consistent approaches to collaborative efforts towards advancing our understanding of the vaginal microbiota and its impact on human health.

The monoclonal antibody 13H11 shares part of its epitope in the HIV-1 gp41 membrane-proximal external region (MPER) with the rare, broadly neutralizing human antibody 2F5. Although 13H11 partially cross-blocked 2F5 binding, 13H11 is non-neutralizing and does not block 2F5 neutralization. We show that unlike 2F5, 13H11 binds to a well-defined helical MPER structure that is consistent with the structure of gp41 in a post-fusion six-helix bundle conformation.

See related article in the "Media Coverage" section of this NewsDigest: "Why so many antibodies fail to protect against HIV infection".

Background Bacterial vaginosis (BV) is a common vaginal infection caused by a lack of endogenous lactobacilli and overgrowth of pathogens that frequently recurs following antibiotic treatment.

Methods A phase 2a study assessed colonization efficiency, safety, tolerability, and acceptability of Lactobacillus crispatus CTV-05 (LACTIN-V) administered by a vaginal applicator. Twenty-four women with BV were randomized in a 3:1 ratio of active product to placebo. Participants used LACTIN-V at 2 × 109 colony-forming units (cfu)/dose or placebo for 5 initial consecutive days, followed by a weekly application over 2 weeks. They returned for follow-up on Days 10 and 28.

Results Sixty-one percent of the 18 women randomized to the LACTIN-V group were colonized with L. crispatus CTV-05 at Day 10 or Day 28. Among LACTIN-V users with complete adherence to the study regimen, 78% were colonized at Day 10 or Day 28. Of the 120 adverse events (AEs) that occurred, 108 (90%) and 12 (10%) were of mild and moderate severity, respectively. AEs were evenly distributed between the LACTIN-V and placebo group. Of the total AEs, 93 (78%) were genitourinary in origin. The most common genitourinary AEs included vaginal discharge (46%), abdominal pain (46%), dysuria (21%), pollakiuria (21%), vaginal odor (21%), and genital pruritus (17%). No grade 3 or 4 AEs or serious AEs occurred and no deep epithelial disruption was seen during colposcopic evaluation. The product was well tolerated and accepted.

Conclusions LACTIN-V colonized well, and was safe and acceptable in women treated for BV.

The limited success of HIV vaccine candidates to date highlights our need to better characterize protective cell-mediated immunity (CMI). While HIV-specific CD8+ T cell responses have been largely defined by measuring IFN-, these responses are not always protective, and it is unclear whether the same epitopes would predominate if other functional parameters were examined. Here, we assessed the epitope-specificity of HIV-specific CD8+ T cell responses by multiparametric flow cytometry, measuring five CD8+ T cell functions (IFN-gamma, MIP-1-beta, TNF-alpha, IL-2 and proliferative capacity) in 24 chronically HIV-infected individuals. Sixty-nine eptiope-specific responses were measured to 50 epitopes within p24. Surprisingly, most epitope-specific responses were IFN-gamma negative (50/69). Many responses had polyfunctional (33%) and proliferative (19%) components. An inverse association between IL-2 and proliferation responses was also observed, contrary to what has been described. We confirm that LTNP have more polyfunctional responses, and also have higher magnitude and broader p24-specific proliferation, IL2 and TNF-alpha production compared to progressing controls. Together, these data suggest that the specificity of CD8+ T cell responses differs depending on immunologic readout, with a 3.5-fold increase in breadth detected by including multiple parameters. Furthermore, identification of epitopes that elicit polyfunctional responses reinforces the need for the comprehensive evaluation of HIV vaccine candidates, and may represent novel targets for CMI-based vaccines.

HIV-AIDS continues to devastate populations worldwide. Recent studies suggest that vaccines that induce beneficial immune responses in the mucosal compartment may improve the efficacy of HIV vaccines. Adenovirus serotype 5 (Ad5)-based vectors remain a promising platform for the development of effective vaccines. In an effort to improve the efficacy of Ad5-based vaccines, even in the presence of pre-existing Ad5 immunity, we evaluated the potential for an Ad5-based HIV vaccine to induce antigen specific immune responses following sublingual administration, a route not previously tested in regard to Ad based vaccines. S.l. vaccination with an Ad5-based HIV-Gag vaccine resulted in a significant induction of Gag specific CTL responses in both the systemic and mucosal compartments. We also show that s.l. immunization not only avoided pre-existing Ad5-immunity, but also elicited a broad repertoire of antigen specific CTL clones. Additionally, we confirm for the first time that oral delivery of a vaccine expressing a potent TLR agonist can stimulate innate immune responses through inductions of cytokines and chemokines and activation of NK cells, NKT cells, and macrophages in vivo. These results positively correlated with improved antigen specific CTL responses. These results could be achieved both in Ad5 naive mice, and in mice with pre-existing immunity to Ad5. The simplicity of the s.l. vaccination regimen coupled with augmentation of TLR dependent pathways active in the oral cavity makes s.l. delivery a promising method for HIV vaccine development specifically, as well many other vaccine applications in general.

Interactions between the Fc segment of IgG and Fc-gamma-Rs on a variety of cells are likely to play an important role in the anti-HIV activity of Abs. Because the nature of the glycan structure on the Fc domain is a critical determinant of Fc-Fc-gamma-R binding, proper Fc glycosylation may contribute to Ab-mediated protection. We have generated five different glycoforms of the broadly HIV-1-neutralizing mAb 2G12 in wild-type and glycoengineered plants and Chinese hamster ovary cells. Plant-derived 2G12 exhibited highly homogeneous glycosylation profiles with a single dominant N-glycan species. Using flow cytometry with Fc-gamma-R-expressing cell lines, all 2G12 glycoforms demonstrated similar binding to Fc-gamma-RI, Fc-gamma-RIIa, and Fc-gamma-RIIb. In contrast, two glycoforms derived from glycoengineered plants that lack plant-specific xylose and core alpha-1,3-fucose, and instead carry human-like glycosylation with great uniformity, showed significantly enhanced binding to Fc-gamma-RIIIa compared with Chinese hamster ovary or wild-type plant-derived 2G12. Using surface plasmon resonance, we show that binding of 2G12 to Fc-gamma-RIIIa is markedly affected by core fucose, irrespective of its plant-specific alpha-1,3 or mammalian-type alpha-1,6 linkage. Consistent with this finding, 2G12 glycoforms lacking core fucose (and xylose) mediated higher antiviral activity against HIV-1 or simian immunodeficiency virus as measured by Ab-dependent cell-mediated virus inhibition. This is, to our knowledge, the first demonstration that specific alterations of Fc glycosylation can improve antiviral activity. Such alterations may result in better immunotherapeutic reagents. Moreover, biasing vaccine-induced immune responses toward optimal Fc glycosylation patterns could result in improved vaccine efficacy.

Activated CD4+ T cells are more susceptible to HIV infection than resting T cells; the reason for this remains unresolved. Induction of CIITA and subsequent expression of the MHC class II isotype HLA-DR are hallmarks of CD4+ T cell activation; therefore, we investigated the role of CIITA expression in T cells during HIV infection. CIITA-expressing SupT1 cells display enhanced virion attachment in a gp160/CD4-dependent manner, which results in increased HIV infection, virus release, and T cell depletion. Although increased attachment and infection of T cells correlated with HLA-DR surface expression, Ab blocking, transient expression of HLA-DR without CIITA, and short hairpin RNA knockdown demonstrate that HLA-DR does not directly enhance susceptibility of CIITA-expressing cells to HIV infection. Further analysis of the remaining MHC class II isotypes, HLA-DP and HLA-DQ, MHC class I isotypes, HLA-A, HLA-B, and HLA-C, and the class II Ag presentation genes, invariant chain and HLA-DM, demonstrate that these proteins likely do not contribute to CIITA enhancement of HIV infection. Finally, we demonstrate that in activated primary CD4+ T cells as HLA-DR/CIITA expression increases there is a corresponding increase in virion attachment. Overall, this work suggests that induction of CIITA expression upon CD4+ T cell activation contributes to enhanced attachment, infection, virus release, and cell death through an undefined CIITA transcription product that may serve as a new antiviral target.

Langerhans cells (LCs) and interstitial dendritic cells (IDCs) may be among the first HIV-1 targets after sexual transmission. We generated cells of these types by differentiation of purified CD34+ cord blood cells. After in vitro infection with R5-tropic strains, we obtained a similar percentage of infected cells for both DC subsets. Moreover, LC infection was not increased by blockage of langerin by anti-langerin. These results indicate that under our experimental conditions, there was no evidence of any preference of HIV replication in LCs versus IDCs. The inhibitory activity of HIV-1-specific IgAs and IgGs against HIV-1 replication in LCs and IDCs was analyzed. We found that neutralizing antibodies inhibit HIV-1 infection of both DC subsets. Interestingly, HIV-1 was inhibited more efficiently by the IgGs than the corresponding IgA, due to a Fc-gamma-receptor-dependent mechanism. Moreover, non-neutralizing inhibitory IgGs were able to inhibit infection of both LCs and IDCs. These results underline the importance of HIV-1 inhibition by the binding of the Fc part of IgGs to Fc-gamma-receptors, and suggest that the induction of neutralizing and non-neutralizing inhibitory IgGs in addition to neutralizing IgAs at mucosal sites may contribute to protection against sexual transmission of HIV-1.

Finding an effective microbicide that could substantially lower women's risk of acquiring HIV infection is an ethical imperative. Women and girls continue to be disproportionally affected by HIV in sub-Saharan Africa. Ethics guidelines for conducting preventive HIV microbicide trials call for steps that intertwine biomedical research and public health. Ethical considerations include adequate studies of the safety of microbicides, the use of placebo controls in future trials once a microbicide is shown to be effective, whether leftover microbicide from a trial that demonstrated efficacy should be made available to the public or used in the control group of a future trial, what preventive measures and treatment should be provided for trial participants during and after the research, and what constitute 'fair benefits' to the community or country when a trial is completed. The Global Campaign for Microbicides conducted a study of the benefits being provided to participants in microbicide trials and others, and found substantial evidence that researchers and sponsors are meeting the obligations stated in ethical guidelines. A cautionary tale of an HIV prevention trial that was prematurely halted demonstrates the need for engagement with the community where trials are carried out.

The envelope glycoprotein (Env) of human immunodeficiency virus is key to viral entry of susceptible target cells and is therefore a major target for the design of vaccines and antiviral drugs. C-C chemokine receptor type 5 (CCR5)-using (R5) Env is the predominant phenotype associated with early transmission and acute infection. This study investigated the mechanism of CCR5 use and the sensitivity to CCR5 inhibitors of a panel of transmitted or early founder (T/F) Envs. The data showed that the majority of T/F Envs used CCR5 and that many also used CCR3, although less efficiently. Despite a similar ability to use wild-type CCR5, individual Envs differed significantly in their sensitivity to the CCR5 inhibitors maraviroc, CMPD-167 and SCH-412147. Inhibitor mapping experiments demonstrated that maraviroc, CMPD-167 and SCH-412147 interfered with the binding of CCR5 mAb to the C-terminal half of the second extracellular loop 2 of CCR5. Interestingly, Envs resistant to maraviroc, CMPD167 and SCH-412147 remained sensitive to TAK-779. Further studies indicated that the sensitivity of Envs to CCR5 inhibitors correlated with the molecular anatomy of CCR5 use, revealing that the inhibitor-sensitive Envs barely used the CCR5 N terminus, whereas resistant Envs showed a marked increase in its use. Taken together, these findings demonstrate that T/F R5 Envs are heterogeneous with respect to the mechanisms of CCR5 utilization. These data may have implications for therapeutic and prophylactic use of CCR5-based antiretrovirals.

Recent advances in human immunodeficiency virus (HIV) vaccine design have resulted in induction of strong CD4 T-cell proliferative and polyfunctional cytokine responses, which are also characteristic for long-term non-progressing (LTNP) HIV-infected individuals. However, limited information is available on the persistence of these responses after infection. Results from studies in non-human primates indicate that vaccine-induced immune responses are partially maintained upon viral infection and differ from the responses seen in non-vaccinated animals that typically progress to disease. However, it is unclear how these partially preserved responses compare to immune responses that are acquired naturally by LTNP animals. In this study, immune-response profiles were compared between vaccinated animals that, upon SHIV89.6p challenge, became infected but were able to control virus replication, and a group of animals having spontaneous control of this viral infection. Both groups were found to develop very similar immune responses with regard to induction of CD4 and CD8 T-cell polyfunctional cytokine responses, proliferative capacity and cytotoxic capacity, as measured by a standard 51Cr release assay and more direct ex vivo and in vivo CTL assays. Hence, vaccinated animals that become infected, but control infection, appear to establish immune responses that are similar to those elicited by long-term non-progressors.

Objective To determine the association of reductions in price of antiretroviral drugs and foreign assistance for HIV with coverage of antiretroviral treatment.

Design Retrospective study.

Setting Africa.

Participants 13 African countries, 2003-8.

Main outcome measures A price index of first line antiretroviral therapy with data on foreign assistance for HIV was used to estimate the associations of prices and foreign assistance with antiretroviral coverage (percentage of people with advanced HIV infection receiving antiretroviral therapy), controlling for national public health spending, HIV prevalence, governance, and fixed effects for countries and years.

Results Between 2003 and 2008 the annual price of first line antiretroviral therapy decreased from $1177 (British Pounds 733; Euros 844) to $96 and foreign assistance for HIV per capita increased from $0.4 to $13.8. At an annual price of $100, a $10 decrease was associated with a 0.16% adjusted increase in coverage (95% confidence interval 0.11% to 0.20%; 0.19% unadjusted, 0.14% to 0.24%). Each additional $1 per capita in foreign assistance for HIV was associated with a 1.0% adjusted increase in coverage (0.7% to 1.2%; 1.4% unadjusted, 1.1% to 1.6%). If the annual price of antiretroviral therapy stayed at $100, foreign assistance would need to quadruple to $64 per capita to be associated with universal coverage. Government effectiveness and national public health expenditures were also positively associated with increasing coverage.

Conclusions Reductions in price of antiretroviral drugs were important in broadening coverage of HIV treatment in Africa from 2003 to 2008, but their future role may be limited. Foreign assistance and national public health expenditures for HIV seem more important in expanding future coverage.

The Center for Health and Gender Equity (CHANGE) and International Community of Women Living with HIV and AIDS - Global  (ICW Global) invite you to a World AIDS Day event with Dr. Jennifer Hirsch and the team of authors behind The Secret: Love, Marriage, and HIV.

Kaiser Family Foundation Barbara Jordan Conference Center
1330 G Street NW, Washington, D.C.
Wednesday, December 1
4:00 p.m. - 6:00 p.m.

For many women around the world, their greatest risk of contracting HIV comes from having sex with their husbands or long-term partners. In response to this troubling fact, a team of medical anthropologists, led by Dr. Jennifer Hirsch of Columbia University's Mailman School of Public Health and funded by NIH, explored the realities of marital HIV risk, fidelity, and extramarital sex in five diverse settings: Mexico, Nigeria, Uganda, Vietnam, and Papua New Guinea. Their new book, The Secret: Love, Marriage, and HIV (Vanderbilt University Press, 2010) details the social forces that motivate and sometimes demand infidelity. They conclude that HIV prevention messages that associate infidelity with immorality are in some cases incompatible with cross-culturally variable notions of marriage. In the context of U.S. global HIV prevention strategy, for which to "be faithful" remains a cornerstone, these findings shed light on the potential negative consequences of public health prevention policies and programs that imply that marital sex is safe(r) sex. The panel discussion will be followed by a reception. For more information or to RSVP, please contact Ginna Anderson at ganderson@genderhealth.org or 202.393.5930.

Tuesday, November 30, 2010
10am - 12pm
The Embassy of South Africa, 3051 Massachusetts Avenue NW, Washington, D.C. 20008

This event will describe the implications of and next steps following the landmark CAPRISA 004 microbicide trial, conducted by the Centre for the AIDS Programme of Research in South Africa (CAPRISA). Particular attention will be given to women's vulnerability to HIV and the challenges of ensuring access to effective prevention products. A key focus of the discussion will be on lessons learned from the successful collaboration between the US and South Africa in promoting country ownership and the extensive cooperation among sectors and across continents.

Click here to RSVP.

The International Council of AIDS Service Organizations (ICASO) International and Regional Secretariats and sub-regional partners are working with national partners in 15 countries to support the community sector to document, provide critical analysis, and undertake policy dialogue for accountability on achieving Universal Access commitments. This project is supported by the Canadian International Development Agency of the Government of Canada (CIDA) and the Ford Foundation. ICASO would like to thank the UNAIDS Secretariat for facilitating access to relevant information. For more information on how you can contribute or to access the methodology, see: http://www.icaso.org/publications/2010/2010_Tool-research-UA-project.pdf.

On behalf of the Global Commission on HIV and the Law, this is a Call for Submissions for the Commission's Asia-Pacific Regional Dialogue. The first Regional Dialogue for the Asia-Pacific will take place on 24-25 February 2011 in Bangkok, Thailand. In addition to giving voice to regional and country perspectives on issues of HIV and the law, the dialogue aims to contribute to regional efforts for creating enabling legal environments which support effective HIV responses.

How to Submit
Instructions on how to submit can be found in the Call for Submissions. The English version of the Call for Submissions can be found at: http://www.hivlawcommission.org/images/stories/rd_asiapacific_call_en.pdf.