The Weekly NewsDigest is a compilation of HIV prevention research media coverage and relevant science in peer-reviewed journals; material on
other reproductive health issues; and matters of policy and politics relevant to HIV prevention research, development and advocacy.
Its purpose is to raise awareness around the range of opinions and information about HIV prevention research disseminated in the press and
scientific journals and provide a neutral, objective basis for decision-making and evidence-based advocacy.
Laws that reinforce HIV-related stigma and prejudice impede both HIV prevention efforts and access to treatment. They do so by making populations at particular risk of infection (including injecting drug users, men who have sex with men, migrants and sex workers) harder to reach, and by sustaining the social and economic exclusion of people living with HIV (PLHIV).
Despite strong empirical evidence to this effect, countries across the world persist in the enforcement of existing discriminatory and punitive laws, and in introducing new ones. Particularly egregious examples include the criminalisation of drug use, homosexuality and sex work, the failure to provide needle exchange programmes or safe injection sites for injecting drug users and the criminalisation of non-intentional HIV exposure and transmission (including, in some parts of Africa, of women who transmit HIV to their infant children).
Is AIDS still an emergency? How you answer that question probably says a lot about whether you think U.S. President Barack Obama's approach to fighting HIV/AIDS abroad is a good idea or a dangerous detour.
In recent weeks, a growing number of organizations have stepped forward to criticize the Obama administration for allegedly backtracking on a global health battle the world was starting to win. Groups as diverse as Medecins Sans Frontieres and the Congress of South African Trade Unions argue that Obama is flat-lining funding for lifesaving anti-retroviral (ARV) treatments, just as the financial crisis is biting hard at other international funding too. They worry that the world could start to lose momentum, failing to keep up with the epidemic's alarming advance.
The U.S. administration counters that more money than ever is going into global health -- it's just no longer myopically focused on HIV/AIDS. The United States responded to the HIV/AIDS emergency a decade ago, the policy's defenders say; now it's time to take a broader, more sustainable approach that can eventually move patients away from their reliance on the United States. As congressional appropriations come up for 2011, battle lines are being drawn.
Efforts to prevent the spread of HIV in Asia-Pacific must be urgently adapted to target a greater number of women as they are getting infected at a faster rate and pass on the virus that causes AIDS to their children, a U.N. gender expert said. Women accounted for 35 percent of new infections in Asia-Pacific in 2007, up from 18 percent in 1990, according to U.N. agency UNAIDS.
"Given the volume of the population in the region, a 1 percent increase in prevalence means many, many people," UNAIDS' Asia-Pacific gender adviser Jane Wilson told AlertNet in an interview. "If China and India's national responses don't include effective engendered AIDS response, then millions of women will be needlessly infected."
The main drivers behind the spread of HIV among women in the region are unprotected sex and infection by their long-term male partners, particularly if the men are drug users who use contaminated needles, have sex with men or buy sex. Women in abusive relationships are many times more likely to get the virus from their partners, the United Nations has found. Moreover, cultural restrictions on women's freedom of movement and their lesser standing in society in Asia-Pacific mean that they do not get tested as regularly as men and many can't afford health services at all. And HIV/AIDS is still seen as a predominantly male problem.
Research in mice suggests that scientists may have a new lead on using gene therapy against the virus that causes AIDS. The researchers tinkered with human stem cells and then inserted them into mice where they multiplied into immune system cells that provided protection against infection with HIV, according to a study released online July 2 in Nature Biotechnology.
The results are unlike typical research in animals because the mice have been "humanized": They have human immune systems and resisted a human disease. Still, until research is conducted on humans, there's no way to know if the treatment will work in people. And it may be years until that happens. But there are high hopes. "It's a one-shot treatment if it works," noted study co-author Paula Cannon, associate professor of molecular microbiology at the University of Southern California.
In gene therapy, doctors try to coax the human body into doing something differently by tweaking its genetic structure. To treat HIV, the virus that causes AIDS, scientists have been experimenting with using gene therapy to boost the immune system. In the new study, researchers engineered human stem cells -- cells that create other cells -- to lock a kind of "door" that allows HIV to enter. The door, a "receptor" on immune cells linked to a gene known as CCR5, is disabled in a very small percentage of people, and those people appear to be virtually immune to HIV.
Click here to read the full article in Nature Biotechnology; see "Published Research" below for abstract.
In the Zulu heartland of South Africa, where more than one in seven people are HIV positive, a Zulu king is reviving the tradition of male circumcision in an effort to fight the spread of HIV. In the province of KwaZulu-Natal everyday around 350 people are infected with HIV, and more than 320 people die from AIDS-related diseases.
But 18-year-old Nhlonipho Mchunu says he's determined not to be another statistic. That's why he has decided to be circumcised. "I know it's not painful," Mchunu told CNN. "There's no reason to be scared, because this thing, it's going to help you. Circumcision is going to help me."
In this Zulu stronghold circumcision was long ago a tradition among young men. Now, with his people suffering from the highest rates of infection anywhere in South Africa, Zulu king Goodwill Zwelithini wants to revive the practice. "I don't want to lose any of my Zulu people," he told CNN. "As I've revived this circumcision, I'm showing my love to my people. Let's hold our hands together. But you young ones, accept -- listen to your king's call."
Binti Omar waits anxiously for her HIV test in a tent erected as part of a testing drive being conducted by the Council of Imams and Preachers of Kenya (CIPK) in the coastal city of Mombasa; Omar is accompanied by her fiance, Abubakar Ismael, and his two wives. "I'm about to be part of Abu's larger family, so we found it necessary to come here and get ourselves tested so that we can plan our future much better," Omar said. "Life nowadays is so risky... It would be good for us all to get to know each other's HIV status."
Ismael and his family, as well as hundreds of other locals, are getting tested at the CIPK camps in response to calls by imams -- Muslim scholars -- in mosques in Kenya's largely Muslim Coast Province. Outgoing Chief Kadhi Sheikh Ahmed Kassim recently led some imams and locals in getting tested for HIV. He noted that the camps, held with the joint US-Kenya government programme, AIDS Population and Health Integrated Assistance in Kenya's Coast Province, APHIA II, were meant to enlighten and encourage Muslim youths, couples and Kenyans in general on the importance of getting tested.
The upcoming 18th annual International AIDS Conference should focus on reaching the most vulnerable populations and removing barriers to their treatment, Human Rights Watch said today. With its theme of "Rights Here Right Now," the conference, which opens in Vienna on July 18, 2010, will bring together more than 25,000 scientists, government leaders, and AIDS activists from around the world to examine the successes and shortcomings of the global AIDS response.
"The conference is about HIV/AIDS and human rights," said Joe Amon, director of health and human rights at Human Rights Watch. "But with 3 million new HIV infections each year, talking about rights won't do the job. We need action and accountability." Advances in science and medicine will have limited impact without changing the harmful laws and policies that drive people who are at risk away from HIV testing and prevention, and that make it hard for those who need treatment to get it, Human Rights Watch said.
A team of researchers from UNC are six years into a study on new approaches to early HIV detection and prevention. And with a $1.7 million grant from the U.S. Centers for Disease Control and Prevention, the study is set to expand. The study will explore new testing methods for catching the infection earlier, determine cost-effectiveness and performance of new HIV detection tests and establish a social networking campaign to improve the process of partner notification. Peter Leone, a professor in the UNC School of Medicine, is one of three co-principal investigators for the study. "The main purpose of the study is to find ways to interrupt the spread of HIV," Leone said.
When a person first contracts HIV is when they are most likely to spread it to their partner. As it takes time for the body to develop antibodies for any new virus, it is often difficult to detect infection immediately. In the four- to eight-week period after infection and before detection of HIV antibodies, Leone said, the virus replicates rapidly, and there is a much higher probability of unknowingly transmitting the virus. "The 4th generation assay allows you to both look for antibodies and for the virus itself," Leone said, adding that the new method helps to speed up the diagnostic process. "The four to eight weeks is reduced to seven to 14 days. That means we can pick up people we would have otherwise missed."
Like so many young mothers in this country, Vicki Achieng, 35, is a widow. Her husband died of AIDS two years ago. He left her a vegetable farm and five young children to help her work it."Life is very difficult without a husband, you know?" she explains wistfully, her lilting Luo accent tinged with sadness. "I miss him so much!"
Achieng knew even before her husband died that he had infected her with HIV. "So many people have it, and so many people are living with it," she shrugs. "We cannot run from it. We are coping with it." She had little choice but to accept her fate and raise her children. She could not possibly afford the expensive antiretroviral medicines that could keep her HIV disease in check, and even if she could, there was nowhere to get them, no doctor to prescribe them.
Then she heard about a new clinic in Kisumu, not far from the rocky shores of Lake Victoria in western Kenya's Nyanza province. The clinic, set up by doctors from UCSF and the Kenya Medical Research Institute, is having a dramatic impact -- "literally resurrecting the dead," says Charles Muga, one of the Kenyans who works there. The clinic has become a model of how to finally reverse years of spiraling AIDS death rates in sub-Saharan Africa -- a model that the U.S. government is ready to replicate throughout Kenya.
When HIV was first discovered to cause AIDS in 1981, prominent scientists expected to have an effective vaccine within a couple of years. Three decades later, the disease has killed more than 25 million people and defied every effort so far to inoculate against it. But researchers at Rockefeller University are launching a new clinical trial that they hope will mark a turning point in the struggle to develop an effective vaccine against the deadly disease. Building on more than 15 years of research, they are testing a first of its kind vaccine that directly taps the power of the cells that that orchestrate the body's immune response, called dendritic cells.
"We have good reason to believe that this novel effort targeting dendritic cells could significantly improve the quality of the immune response to HIV," says Sarah Schlesinger, associate professor of clinical investigation, who is leading the study. Dendritic cells were originally discovered in 1973 at Rockefeller by Zanvil A. Cohn and Ralph M. Steinman, now head of the Laboratory of Cellular Physiology and Immunology. Over the years, these cells have been shown to coordinate the immune response, processing foreign substances like viruses or other infections and training the immune system's T cells to kill them. "We know that every vaccine works through dendritic cells in some way, we just haven't fully understood how," Schlesinger says. "Now we're going straight to the source."
The Zimbabwe government's male circumcision programme has so far reached 6 500 men with the oldest being a 70 year old. This figure has more than doubled from last year's figures of 3 000 men when the programme was launched. The government is targeting to reach 80 percent of men aged from 15 to 29 years by 2015, about three million men, as a way to reduce HIV transmission in the country. However the programme has been hit by a critical human resource constraint because of lack of incentives. So far 104 doctors have been trained but only few of these are performing the operations. Updating stakeholders on the achievements of the programme, Ministry of Health and Child Welfare National HIV Prevention Coordinator AIDS & TB Unit, Getrude Ncube, said there was a low uptake of the programme by the few doctors who were trained to do the operations.
Two leading HIV researchers say that countries worst affected by HIV should test whether promoting a national month of sex abstinence could slow the spread of HIV, by interrupting the chain of transmission during the primary, highly infectious stage of HIV infection. Professor Alan Whiteside of the Health Economics and HIV/AIDS Research Division (HEARD) at the University of Kwazulu-Natal and Dr Justin Parkhurst of the London School of Hygiene and Tropical Medicine (LSHTM) say that if mathematical modelling shows the idea to have possibilities, national campaigns to test the hypothesis should follow. Swaziland is already considering the idea, Professor Whiteside says.
HIV levels are highest in the month to six weeks after infection, before immune responses begin to control the virus. Individuals in this phase of infection may account for anywhere from 10-45% of new HIV infections. Stopping large numbers of recently infected people from passing on the virus for a month could act as a 'fire break', in the same way that trees are chopped down in a forest fire to break the progress of the fire.
Over a glass of wine in a bar in Kampala, the Ugandan capital, two young women have a heated discussion about Tim*, who is married to their friend Becky*; Tim's "side-dish", or mistress, is pregnant and the two women disagree over whether Becky should leave him or not.
"Becky knew what to expect when she married him; she shouldn't be surprised," one of the women says. "No way - it's one thing to cheat, but for him not to wear a condom means he doesn't care about Becky at all... Next she could find out she has HIV," the other said. While the women were at odds over Becky's next move, they both agreed that fidelity was not something one could expect from men in their society.
Since the 1980s, Uganda's HIV prevention campaigns have focused heavily on fidelity to a single sexual partner, with abstinence and condom use being the two other major tenets. However, there has been some debate about whether "multiple concurrent partnerships" are indeed one of the forces behind Africa's epidemic - a 2009 study found "limited evidence" that concurrency was driving HIV/AIDS in Africa - but for many Ugandans, the main problem with "zero-grazing" -- sticking to one sexual partner -- campaigns is their attempt to alter centuries of tradition.
HIV research is undergoing a renaissance that could lead to new ways to develop vaccines against the AIDS virus and other viral diseases. In the latest development, U.S. government scientists say they have discovered three powerful antibodies, the strongest of which neutralizes 91% of HIV strains, more than any AIDS antibody yet discovered. They are now deploying the technique used to find those antibodies to identify antibodies to influenza viruses.
The HIV antibodies were discovered in the cells of a 60-year-old African-American gay man, known in the scientific literature as Donor 45, whose body made the antibodies naturally. The trick for scientists now is to develop a vaccine or other methods to make anyone's body produce them as well. That effort "will require work," said Gary Nabel, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, who was a leader of the research. "We're going to be at this for a while" before any benefit is seen in the clinic, he said.
The research was published Thursday in two papers in the online edition of the journal Science, 10 days before the opening of a large International AIDS Conference in Vienna, where prevention science is expected to take center stage. More than 33 million people were living with HIV at the end of 2008, and about 2.7 million contracted the virus that year, according to United Nations estimates.
A new study has challenged widely held assumptions about income level in relation to HIV, finding that neither wealth nor poverty are reliable predictors of HIV infection in Africa. Previously, the argument that poverty drove HIV epidemics was supported by the World Bank and UNAIDS, as well as less reliable authorities like former South African President Thabo Mbeki, who told the International AIDS Conference in Durban in 2000 that the disease was a partner with "poverty, suffering, social disadvantage and inequity". More recent research suggests that the reality is far more complex. For example, Botswana and South Africa, described as two of the wealthiest countries on the continent, also have among the highest rates of HIV infection.
Nevertheless, the idea that poverty fuels the spread of HIV has persisted as "a very dominant narrative", according to Justin Parkhurst of the London School of Hygiene and Tropical Medicine. Parkhurst analyzed and compared data on HIV and wealth from demographic and health surveys in 12 sub-Saharan African countries with generalized epidemics (national prevalence rates higher than 1 percent); his findings are published in the July issue of the Bulletin of the World Health Organization. He noted that in lower-income countries HIV prevalence tended to rise in tandem with wealth -- in Uganda and Cote d'Ivoire, for example, women in the highest income bracket had the highest HIV prevalence. In countries with a per capita gross domestic product higher than US$2,000, the link between wealth and prevalence was less clear.
Around 70,000 babies are born with HIV in South Africa every year. It is one of the main contributors to the country's high infant mortality rate. In a hopeful sign, programs aimed at preventing the transmission of HIV from mother-to-child are meeting with success. One such program is part of a community-based project called Total Control of the Epidemic (TCE). Total Control of the Epidemic was started in Denmark in 1977 by the organization, Humana People to People. TCE provides care and support to entire communities heavily affected by HIV and AIDS. The program has been operating in South Africa for eight years and has reached more than three million people in five of the country's nine provinces.
A dearth of data, and lack of science-based policymaking, are hampering efforts to combat the HIV/AIDS epidemic in the Middle East and North Africa (MENA), according to a major scientific study. 'Characterizing the HIV/AIDS Epidemic in the Middle East and North Africa: Time for Strategic Action' is the most comprehensive scientific synthesis of HIV spread in the region since the discovery of HIV 25 years ago, according to the Joint UN Programme on HIV/AIDS (UNAIDS). It was launched at the sidelines of an HIV/AIDS policy dialogue meeting in Dubai this week (28-29 June) and produced by the World Bank, in collaboration with UNAIDS and the WHO.
"The basic assumption in the region was that there are no HIV data in MENA," Laith Abu-Raddad, assistant professor of public health at the Infectious Disease Epidemiology Group, at the Qatar-based Weill Cornell Medical College, and the lead author of the report, told SciDev.Net. "The major obstacle [to scientific assessments of HIV/AIDS in MENA] is that people did not believe it was possible."
Africa has quality research and development (R&D) capacity but its distribution is uneven and collaboration across the continent remains poor, according to a study. Researchers in Tunisia and Switzerland assessed Africa's biomedical research landscape as part of the development of the African Network for Drugs and Diagnostics Innovation (ANDI) -- a network that aims to boost African health research through increased funding.
They built a database of peer-reviewed biomedical research articles that featured at least one African author from 2004-2008. Around 2,700 institutions in 47 of Africa's 53 countries were identified that had produced articles published in peer-reviewed journals indicating that "quality R&D capacity exists in the continent". But the distribution of this capacity is uneven: only three African countries -- Egypt, Nigeria and South Africa -- were represented among the 20 most productive institutions. And the authors added that "portions of Western and Central Africa are lagging behind".
'Founder' strain of close cousin of HIV still present months later. Scientists have been surprised to learn that, despite thousands of changes that viruses like HIV undergo in rapid fashion to evade the body's immune system, the original version that caused the infection is still present in the body months later.
The finding, published in the June issue of the Journal of Virology, is the result of an uncommonly detailed look at the cat-and-mouse action that takes place in an organism shortly after infection. The work is aimed at understanding the earliest stages of infection by HIV more thoroughly, to help scientists develop ways either to quash the infection outright or to develop a vaccine to prevent infection.
The research, which was conducted by scientists at the University of Rochester Medical Center, is based on an analysis of more than 100,000 genetic snippets of a virus known as SIV, or simian immunodeficiency virus, which infects monkeys and is a close cousin of HIV.
To read the study in the Journal of Virology, click here.
Researchers conducting local trials to determine if anti-retroviral drugs Tenofovir and Truvada can protect women from acquiring HIV have expressed concern over the rate at which participants in the trials are falling pregnant. Microbicide Trials Network - an arm of the University of Zimbabwe working in collaboration with the University of San Francisco in California -- is conducting the trials. Speaking at MTN's official launch in Harare last week, project director Dr Nyaradzo Mgodi said the prerequisites for women to participate in the ARV-based two-year trial included consistent use of contraceptives.
A top U.S. health official says the first few minutes after HIV infection may be a window of opportunity to prevent the AIDS virus from firmly taking hold in the body. The HIV that's present during initial infection is different from the virus that replicates over time. And that difference is very important. So says Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. "The events that occur within literally minutes to hours from the time a person gets exposed actually determines what's going to happen for that person either getting infected or the nature of the disease and the opportunities to block those early events by either pre-exposure prophylaxis, microbicides or vaccines," he says.
One example of pre-exposure prophylaxis is the use of anti-retroviral drugs as a preventive measure. Currently, the drugs are most often administered after HIV infection is confirmed and the immune system is weakened. Microbicides are a gel, cream or suppository that releases a drug.
Genital warts, commonly caused by human papillomavirus (HPV) are on the decline after routine vaccination of Australian women with a vaccine against HPV. The sexual partners of these women are also beneficiaries of the vaccine. The study was conducted by the University of NSW and it found that since the government-funded vaccination program was launched in mid-2007 there has been a 60% decline in the incidence of these warts. The vaccine (Gardasil) is given to women aged between 12 and 26 to protect them from four strains of HPV that have been linked to cervical cancer and genital warts. The vaccine programme successfully covered 80% of the target population. Even heterosexual men have reaped a 30% benefit from this vaccination programme. The decline was not seen in women over 27 who did not receive the vaccine. Researchers pooled data from eight sexual health clinics Australia-wide, covering 110,000 new patients and the period from 2004 to 2009.
A team of researchers from the University of California San Diego and Mexico has found that even a modest behavioral intervention program averaging just 35 minutes can measurably reduce the incidence of HIV and sexually transmitted infections (STIs) among female sex workers in the U.S.-Mexico border region - and that the program succeeds at comparatively little expense. The findings will be published online by the journal PLoS One on June 30.
"These are important findings," said Thomas Patterson, PhD, professor of psychiatry in the School of Medicine at UC San Diego. "Too often good research sits on a shelf, unimplemented, because it's thought not to be cost-effective. This study shows that a relatively inexpensive intervention program can significantly affect the incidence of HIV and STIs in a high-risk population."
Using a sophisticated modeling system, researchers studied how a hypothetical group of 1,000 female sex workers in the U.S.-Mexico border region would respond to a previously tested behavioral intervention program called Mujer Segura or Healthy Woman. Approximately 35 minutes in length, Mujer Segura employs motivational techniques to encourage female sex workers to use safer sex practices, and teaches better condom negotiation skills with clients who request unprotected sex.
Is Institutional Review Board (IRB) approval and a rigorous informed consent process enough? It is our view that this is no longer the case. Conventional research ethics emphasise the importance of weighing the risks and benefits for prospective participants as one of the key determinants of deeming a clinical trial ethical. We support the notion that ethical obligations of research should include considerations not only at the individual level, but also at the community level (1,2).
As stakeholders in the field of biomedical HIV prevention research, we have seen how the HIV/AIDS pandemic has greatly shaped what is viewed as ethical conduct in research. To assess the effectiveness of new HIV prevention technologies, clinical trials must recruit large numbers of healthy, HIV-negative individuals as study participants. Research ethics stipulate that these new HIV prevention strategies be tested for safety and effectiveness in populations who need these interventions and are likely to use them. Therefore, these trials are conducted often as multi-site, international studies, and with high-incidence populations who may be poor or marginalised and consequently may have less access to standard health care services. Frequently, setting up a biomedical HIV prevention clinical trial is a vast undertaking accompanied by the need for investment in time, human resources and infrastructure. As a result of their size, these trials can have impact on the surrounding community -- a new clinic may be built, jobs may be created and access to better health interventions may become available. The arrival of a large trial, however, if not conducted in ways that are sensitive to the local environment and locally determined priorities, may create conflict or misunderstanding between researchers and the community from which trial participants will be recruited.
HIV-specific T cells response and T cell activation are frequently seen in exposed seronegative individuals (ESN). In this study, we report HIV-specific response and level of T cell activation in ESN partners of HIV-infected patients presenting low or undetectable levels of HIV-RNA. We evaluated 24 HIV-serodiscordant couples. ESN were classified into three categories of exposure to HIV (very low, low, and moderate-high), considering levels of HIV-RNA in their infected partner and frequency of sexual high-risk practices within the last 12 mo. HIV-specific T cell responses and activation levels in T cell subsets were evaluated by flow cytometry. We reported that 54% of ESN had detectable HIV-specific T cells response, being the highest prevalence seen in the low exposure group (64%). Several T cell subsets were significantly increased in ESN when compared with controls: CD4+CD38+ (p = 0.006), CD4+HLA-DR-CD38+ (p = 0.02), CD4+CD45RA+CD27+HLA-DR-CD38+ (p = 0.002), CD8+CD45RA+CD27+CD38-HLA-DR+ (p = 0.02), and CD8+CD45RA+CD27-CD38+HLA-DR+ (p = 0.03). Activation of CD8+ T cells was increased in ESN with detectable HIV T cell responses compared with ESN lacking these responses (p = 0.04). Taken together, these results suggest that persistent but low sexual HIV exposure is able to induce virus-specific T cells response and immune activation in a high proportion of ESN, suggesting that virus exposure may occur even in conditions of maximal viral suppression in the HIV-infected partner.
Objective Male circumcision has been shown to reduce the risk of HIV acquisition among heterosexual men but the impact among men who have sex with men (MSM) is not known. In this paper, we explore the feasibility of research into circumcision for HIV prevention among MSM in Scotland.
Methods Anonymous, self-complete questionnaires and Orasure oral fluid collection kits were distributed to men visiting the commercial gay scenes in Glasgow and Edinburgh.
Results 1508 men completed questionnaires (70.5% response rate) and 1277 provided oral fluid samples (59.7% response rate). Overall, 1405 men were eligible for inclusion in the analyses. 16.6% reported having been circumcised. HIV prevalence was similar among circumcised and uncircumcised men (4.2% and 4.6%, respectively). Although biologically, circumcision is most likely to protect against HIV for men practising unprotected insertive anal intercourse (UIAI), only 7.8% (91/1172) of uncircumcised men reported exclusive UIAI in the past 12 months. Relatively few men reported being willing to participate in a research study on circumcision and HIV prevention (13.9%), and only 11.3% of uncircumcised men did so.
Conclusion The lack of association between circumcision and HIV status, low levels of exclusive UIAI, and low levels of willingness to take part in circumcision research studies suggest circumcision is unlikely to be a feasible HIV prevention strategy for MSM in the UK. Behaviour change should continue to be the focus of HIV prevention in this population.
The identities of the regulators that mediate commitment of hematopoietic precursors to the T lymphocyte lineage have been unknown. The last stage of T lineage commitment in vivo involves mechanisms to suppress natural killer cell potential, to suppress myeloid and dendritic cell potential, and to silence the stem cell or progenitor cell regulatory functions that initially provide T cell receptor-independent self-renewal capability. The zinc finger transcription factor Bcl11b is T cell-specific in expression among hematopoietic cell types and is first expressed in precursors immediately before T lineage commitment. We found that Bcl11b is necessary for T lineage commitment in mice and is specifically required both to repress natural killer cell-associated genes and to down-regulate a battery of stem cell or progenitor cell genes at the pivotal stage of commitment.
CCR5 is the major HIV-1 co-receptor, and individuals homozygous for a 32-bp deletion in CCR5 are resistant to infection by CCR5-tropic HIV-1. Using engineered zinc-finger nucleases (ZFNs), we disrupted CCR5 in human CD34+ hematopoietic stem/progenitor cells (HSPCs) at a mean frequency of 17% of the total alleles in a population. This procedure produces both mono- and bi-allelically disrupted cells. ZFN-treated HSPCs retained the ability to engraft NOD/SCID/IL2r[gamma]null mice and gave rise to polyclonal multi-lineage progeny in which CCR5 was permanently disrupted. Control mice receiving untreated HSPCs and challenged with CCR5-tropic HIV-1 showed profound CD4+ T-cell loss. In contrast, mice transplanted with ZFN-modified HSPCs underwent rapid selection for CCR5-/- cells, had significantly lower HIV-1 levels and preserved human cells throughout their tissues. The demonstration that a minority of CCR5-/- HSPCs can populate an infected animal with HIV-1-resistant, CCR5-/- progeny supports the use of ZFN-modified autologous hematopoietic stem cells as a clinical approach to treating HIV-1.
The administration of antiretrovirals before HIV exposure to prevent infection (i.e., preexposure prophylaxis; PrEP) is under evaluation in clinical trials. Because PrEP is based on antiretrovirals, there is considerable concern that it could substantially increase transmitted resistance, particularly in resource-rich countries. Here we use a mathematical model to predict the effect of PrEP interventions on the HIV epidemic in the men-who-have-sex-with-men community in San Francisco. The model is calibrated using Monte Carlo filtering and analyzed by constructing nonlinear response hypersurfaces. We predict PrEP interventions could substantially reduce transmission but significantly increase the proportion of new infections caused by resistant strains. Two mechanisms can cause this increase. If risk compensation occurs, the proportion increases due to increasing transmission of resistant strains and decreasing transmission of wild-type strains. If risk behavior remains stable, the increase occurs because of reduced transmission of resistant strains coupled with an even greater reduction in transmission of wild-type strains. We define this as the paradox of PrEP (i.e., resistance appears to be increasing, but is actually decreasing). We determine this paradox is likely to occur if the efficacy of PrEP regimens against wild-type strains is greater than 30% and the relative efficacy against resistant strains is greater than 0.2 but less than the efficacy against wild-type. Our modeling shows, if risk behavior increases, that it is a valid concern that PrEP could significantly increase transmitted resistance. However, if risk behavior remains stable, we find the concern is unfounded and PrEP interventions are likely to decrease transmitted resistance.
During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. Here, we determine the crystal structure of VRC01 in complex with an HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through V-gene-derived regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.
Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1-infected subjects, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope (Env) structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of CD4 receptor binding. These probes were used to identify sera with NAbs to the CD4-binding site (CD4bs) and to isolate individual B cells from such an HIV-1-infected donor. By expressing immunoglobulin genes from individual cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of gp120, an important insight for future HIV-1 vaccine design.
Editor's note: This paper is part of a PLoS Medicine series on maternal, neonatal, and child health in Africa.
This PLoS Medicine series began by outlining how much we fail mothers, newborns, and children in Africa by not implementing effectively what we know saves lives and improves health. It is clear that countries in Africa are falling behind not only on improving maternal, newborn, and child health but on the Millennium Development Goals 4, 5, and 6 more generally. Why is there such a wide gap between what we know and what we do? While technical knowledge about what could be done is available, actual implementation is neither straightforward nor easy in the often difficult circumstances on the ground. The many competing priorities -- along with limited logistic capacity, a lack of political will, and inadequate infrastructure -- also constrain the extent to which effective health packages are delivered to those who need them most.
Objective To conduct a systematic review of the literature to examine HIV vaccine acceptability and factors impacting acceptability of future HIV vaccines.
Design Systematic review and meta-analysis of peer-reviewed articles that assessed HIV vaccine acceptability.
Methods We used a comprehensive search strategy across multiple electronic databases to locate original quantitative or qualitative studies that examined rates or correlates of HIV vaccine acceptability. We conducted meta-analysis on studies reporting correlates or predictors of HIV vaccine acceptability.
Results Twenty studies (n = 7576) reported HIV vaccine acceptability ranging from 37.2 to 94.0 on a 100-point scale; weighted mean acceptability = 65.6 (SD = 21.1). Eleven studies compared HIV vaccine acceptability at high (80-95%) efficacy (mean = 73.8; SD = 9.2) versus moderate (50%) efficacy (mean = 40.4; SD = 20.2). Among 13 studies (n = 5023) included in meta-analysis, efficacy and non'risk group' membership had medium effect sizes, and pragmatic obstacles, cost, perceived susceptibility to HIV infection, side effects/safety concerns, fear of vaccines, perceived vaccine benefits, duration of protection, and ethnicity had small effect sizes on HIV vaccine acceptability.
Conclusion Public health strategies to promote the benefits of partial efficacy HIV vaccines and accurate HIV risk perceptions, and to dispel vaccine fears, along with structural interventions to subsidize vaccine costs and facilitate access, may increase future HIV vaccine uptake and, in turn, the effectiveness of HIV vaccines in controlling the epidemic.
When Meena Seshu first entered a brothel in rural India, she was expecting a melodramatic scene from a Bollywood film, in which poor helpless women were being victimised by brutal, aggressive men. Seshu, who runs SANGRAM, an Indian non-governmental organisation (NGO) that works with sex workers to stop the spread of HIV/AIDS, soon found that the reality was rather different. These women were, for the most part, in control of their lives, but through a combination of prejudice and fear were being mistreated by every section of society. SANGRAM, based in rural Maharashtra, which seeks to empower the women to form collectives and fight for their human rights, came along at the right time.
But SANGRAM's initial remit when it was set up in 1992 was more concerned with ensuring that sex workers didn't spread HIV through migrant workers to "good women". Its evolution into a more enlightened entity has much to do with Seshu, whose career path has zig-zagged across disciplines. After a degree in life sciences and a masters in social work, she worked as a social worker with widows and abandoned women, later becoming a science teacher, and then a newspaper reporter writing about HIV. But Seshu, who grew up in a wealthy part of Mumbai, says she had to work hard to gain the trust of the women she works with.
Sex workers, used to being exploited by most of society, are notoriously closed in their dealings with the outside world. Seshu realised that "fostering a sense of community would be crucial in ensuring that their HIV prevention programme was effective". The organisation has helped create a collective of 5000 women (called VAMP) working in prostitution from seven districts across Maharashtra and the neighbouring state of Karnataka. SANGRAM, which means "struggle", works with the women to ensure that they are accorded the sexual and human rights they deserve.
Background We investigated the impact of antimicrobials in cervicovaginal lavage (CVL) from HIV(+) and HIV(-) women on target cell infection with HIV. Since female reproductive tract (FRT) secretions contain a spectrum of antimicrobials, we hypothesized that CVL from healthy HIV(+) and (-) women inhibit HIV infection.
Methodology/Principal Findings CVL from 32 HIV(+) healthy women with high CD4 counts and 15 healthy HIV(-) women were collected by gently washing the cervicovaginal area with 10 ml of sterile normal saline. Following centrifugation, anti-HIV activity in CVL was determined by incubating CVL with HIV prior to addition to TZM-bl cells. Antimicrobials and anti-gp160 HIV IgG antibodies were measured by ELISA. When CXCR4 and CCR5 tropic HIV-1 were incubated with CVL from HIV(+) women prior to addition to TZM-bl cells, anti-HIV activity in CVL ranged from none to 100% inhibition depending on the viral strains used. CVL from HIV(-) controls showed comparable anti-HIV activity. Analysis of CH077.c (clone of an R5-tropic, mucosally-transmitted founder virus) viral inhibition by CVL was comparable to laboratory strains. Measurement of CVL for antimicrobials HBD2, trappin-2/elafin, SLPI and MIP3[alpha] indicated that each was present in CVL from HIV(+) and HIV(-) women. HBD2 and MIP3[alpha] correlated with anti-HIV activity as did anti-gp160 HIV IgG antibodies in CVL from HIV(+) women.
Conclusions/Significance These findings indicate that CVL from healthy HIV(+) and HIV(-) women contain innate and adaptive defense mechanisms that inhibit HIV infection. Our data suggest that innate endogenous antimicrobials and HIV-specific IgG in the FRT can act in concert to contribute toward the anti-HIV activity of the CVL and may play a role in inhibition of HIV transmission to women.
We recently reported that rhesus macaques inoculated with CD4 binding-competent and CD4 binding-defective soluble YU2-derived HIV-1 envelope glycoprotein (Env) trimers in adjuvant generate comparable levels of Env-specific binding antibodies (Abs) and T cell responses. We also showed that Abs directed against the Env co-receptor binding site (CoRbs) were only elicited in animals immunized with CD4 binding-competent trimers and not in animals immunized with CD4 binding-defective trimers, indicating that a direct interaction between Env and CD4 occurs in vivo. To investigate both the overall consequences of in vivo Env-CD4 interactions and the elicitation of CoRbs-directed Abs for protection against heterologous SHIV challenge, we exposed rhesus macaques immunized with CD4 binding-competent and CD4 binding-defective trimers to the CCR5-tropic SHIV-SF162P4 challenge virus. Compared to unvaccinated controls, all vaccinated animals displayed improved control of plasma viremia, independent of the presence or absence of CoRbs-directed Abs prior to challenge. Immunization resulted in plasma responses that neutralized the heterologous SHIV challenge stock in vitro, with similar neutralizing Ab titers elicited by the CD4 binding-competent and CD4 binding-defective trimers. The neutralizing responses against both the SHIV-SF162P4 stock and a recombinant virus pseudotyped with a cloned SHIV-SF162P4-derived Env were significantly boosted by the SHIV challenge. Collectively, these results suggest that the capacity of soluble Env trimers to interact with primate CD4 in vivo, and to stimulate the production of moderate titers of CoRbs-directed Abs, did not influence the magnitude of the neutralizing Ab recall response after viral challenge or the subsequent control of viremia in this heterologous SHIV challenge model.
Research on hygiene has been relatively limited in the current era of rigorous observational studies and clinical trials. We set out to investigate the perception and practices of genital hygiene among fishermen working on the beaches along Lake Victoria, targeted for a topical male microbicide hygiene intervention. We conducted 12 focus group discussions involving fishermen (n = 130), recording the discussions in Dholuo (the local language) and transcribing them verbatim before translating into English. Transcripts were double-coded and analysed using constant comparative analysis. Despite easy access to lake water and recognition of a link that may exist between poor genital hygiene and the risk of penile infection and poor sexual relationships, few fishermen regularly washed their genitalia due to fear/embarrassment from cleaning their genitalia in public, traditional Luo beliefs such as that washing with soap would reduce the fish catch, lack of time because of their busy schedules, laziness and lack of responsibility, and excessive consumption of alcohol and illicit drugs. Hygiene practices of the fishermen were poor and could contribute to genital infections including sexually transmitted infections. Given the fishermen's poor genital hygiene practices, they may benefit from hygiene intervention, including that provided by penile microbicides, which can be applied in the privacy of their bedrooms.
Dendritic cells (DCs) contribute to human immunodeficiency virus type 1 (HIV-1) transmission and dissemination by capturing and transporting infectious virus from the mucosa to draining lymph nodes, and transferring these virus particles to CD4+ T cells with high efficiency. Toll-like receptor (TLR)-induced maturation of DCs enhances their ability to mediate trans-infection of T cells and their ability to migrate from the site of infection. Because TLR-induced maturation can be inhibited by nuclear receptor (NR) signaling, we hypothesized that ligand-activated NRs could repress DC-mediated HIV-1 transmission and dissemination. Here, we show that ligands for peroxisome proliferator-activated receptor gamma (PPAR[gamma]) and liver X receptor (LXR) prevented proinflammatory cytokine production by DCs and inhibited DC migration in response to the chemokine CCL21 by preventing the TLR-induced upregulation of CCR7. Importantly, PPAR[gamma] and LXR signaling inhibited both immature and mature DC-mediated trans-infection by preventing the capture of HIV-1 by DCs independent of the viral envelope glycoprotein. PPAR[gamma] and LXR signaling induced cholesterol efflux from DCs and led to a decrease in DC-associated cholesterol, which has previously been shown to be required for DC capture of HIV-1. Finally, both cholesterol repletion and the targeted knockdown of the cholesterol transport protein ATP-binding cassette A1 (ABCA1) restored the ability of NR ligand treated cells to capture HIV-1 and transfer it to T cells. Our results suggest that PPAR[gamma] and LXR signaling up-regulate ABCA1-mediated cholesterol efflux from DCs and that this accounts for the decreased ability of DCs to capture HIV-1. The ability of NR ligands to repress DC mediated trans-infection, inflammation, and DC migration underscores their potential therapeutic value in inhibiting HIV-1 mucosal transmission.
As the leading federal institute for HIV/AIDS research, NIAID is committed to finding a safe and effective vaccine to prevent HIV infection. In 2009, the field of HIV vaccine research experienced significant progress -- a major clinical study in Thailand funded in large part by NIAID demonstrated for the first time that an experimental vaccine could prevent HIV infection among some people. Further, scientists at NIAID and elsewhere discovered several new antibodies capable of neutralizing diverse HIV strains circulating throughout the world. NIAID is building on these achievements through a sustained commitment to pursuing both basic and vaccine discovery research while continuing to advance the most promising HIV vaccine candidates into testing.
There are many challenging questions about HIV that, if answered, could help bring us closer to finding a highly effective vaccine to prevent infection. Among these questions: how can we protect against the wide range of HIV strains that are present among the world's HIV-infected populations? How can a vaccine induce antibodies that can eradicate the virus from the human body once it has entered? What specific types of immune responses are needed to prevent HIV infection?
Program Announcement (PA) Number: PAS-10-226 Application Due Date(s): October 16, 2010; October 16, 2011, October 16, 2012 for new applications; November 16, 2010; November 16, 2011; November 16, 2012 for resubmission applications AIDS Application Due Date(s): January 7, 2011; January 7, 2012; January 7, 2013
Purpose: The purpose of this Funding Opportunity Announcement (FOA), issued by the Office of Research on Women's Health (ORWH) and co-sponsoring NIH institutes and centers (ICs), is to promote innovative, interdisciplinary research that will advance new concepts in women's health research and the study of sex/gender differences. Recent research reports have established the importance of studying issues specific to women, including the scientific and clinical importance of analyzing data separately for females and males. ORWH is particularly interested in encouraging extramural investigators to undertake new interdisciplinary research to advance studies on how sex and gender factors affect women's health; however, applications in all areas of women's health and/or sex/gender research are invited.
In this issue you'll find a brief review of highlights from the biannual International Microbicides Conference (M2010) held in May, including discussions of the potential opportunities and challenges of ARV-based prevention in topical and oral forms, new developments in delivery systems for microbicides and increasing recognition of rectal microbicides as a key area for exploration. Also covered in this issue is what to expect in July at the XVIII International AIDS Conference in Vienna, which will include a wide range of sessions central to the field, including the of results from the CAPRISA 004 trial--the first effectiveness trial of an ARV-based microbicide. See the Not to be Missed section for details on this and other important conference events. And, go to www.avac.org/AIDS2010 for a roadmap to HIV prevention research symposiums, sessions and satellites at the conference.
As usual, this issue includes an up-to-date comprehensive prevention research map and a timeline of large-scale biomedical HIV prevention trials worldwide. Additional resources including the Px Wire archive, information about subscribing, reprint requests and bulk orders can be found at www.avac.org/pxwire.