7 MAY 2010, VOLUME 11, ISSUE 15

A new crystal structure of an anti-HIV-1 envelope antibody bound to an envelope-receptor complex shows the antibody binding both the HIV-1 envelope and the CD4 receptor, raising the question of what the role of antibody autoreactivity in host responses to HIV-1 may be.
     The antibody response to HIV-1 seems to be peculiar in that, unlike influenza, neutralizing antibodies take a relatively long time (3-6 months) to develop against the transmitted/founder strain of HIV-1 (ref. 1); when they do first develop, HIV-1 envelope protein (Env) gp120 neutralizing antibodies that target the transmitted/founder virus are quite strain or type specific.

A common goal in HIV/AIDS research is to control and ultimately end the pandemic, according to Anthony Fauci, MD, director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, speaking at a briefing last week. The briefing was held in collaboration with Representatives Rosa DeLauro, Barbara Lee, and Elliot Engel and was cosponsored by amfAR, the Foundation for AIDS Research; AVAC; HIV Medicine Association; IDSA/HIVMA Center for Global Health Policy; the San Francisco AIDS Foundation; and the Treatment Action Group.
     Although the advances have been "stunning," there's an impression "that we really have our arms around this and that things are stable - and they are not," Dr. Fauci said. Currently, worldwide, there are 2.7 million new infections each year, "which is still really completely and totally unacceptable," he said. In the United States, 56,300 new infections are reported each year, and 1.1 million people are living with HIV, of whom 20% do not know they are infected. According to Dr. Fauci, the common goal of controlling and ending the HIV/AIDS pandemic can be manifested by concentrating on 3 areas: scaling up delivery of proven therapies, curing existing infections, and preventing new infections.

Scaling up Delivery
More than 30 effective antiretroviral drugs are approved for use in HIV/AIDS, and these have "totally transformed the lives of HIV-infected individuals," Dr. Fauci said. "We went from a 26-week lifespan to a 40-year-plus life span" for those infected with the virus. However, in low- to middle-income countries, only 30% to 40% of people who could benefit from antiretroviral therapy are actually receiving it. More sobering, said Dr. Fauci, is that for every person put on antiretroviral therapy in 2008, 2 to 3 people were infected with HIV. "We are not winning the game," he said.

Seeking a Cure
Dr. Fauci also pointed out that some have thought that a cure "is an impossible goal," but that this is not necessarily the case. Although vaccines have produced disappointing results, there is great hope of a "functional cure," in which HIV patients are treated early and aggressively and then go into permanent remission without viral replication.

Preventing New Infections
Dr. Fauci described a third strategy of preventing new infections as being "critical" and "eminently feasible." It includes use of microbicides, male circumcision, blood supply screening, and the use of clean syringes and condoms. However, despite the efficacy of these approaches, only about 20% of people at risk for HIV infection currently have access to prevention approaches.
     Other approaches currently under evaluation include use of treatment as prevention; for example, microbicides that incorporate antiretrovirals into gels, such as 1% tenofovir gel, as well as oral agents used as preexposure prophylaxis, and "test and treat" strategies, in which treatment of all people at risk in theory may prevent spread of infection.
     Trials of vaccines may be beginning to show promise after years of failure. "Last year for the first time we had the first signal of a success in a vaccine trial," Dr. Fauci said. The trial, conducted in Thailand, included 16,000 persons and showed a "modest" 31% efficacy for acquisition of infection. A key question will be to understand why those 31% were protected in the trial, Dr. Fauci said.

Bright spent two years in Zambia's Lusaka Central Prison for selling cannabis but fears he now faces a life sentence. "I did it because of hunger," says Bright softly. "There's not much food in prison. Sex has become the way of payment."
     "Conditions were bad," he remembers. "We had nshima [maize meal] and beans two times a day. I never felt full." One day, the cell "captain" gave Bright extra food, then asked him for sex. "I had never had sex with a man, but I did it. The first time it was painful, but I joined a group of maybe 20 men who did that. "Mainly they were people who were condemned, or who had been jailed for 25 years. They hadn't seen women for a long time."

Biggest risk factor
He fidgets as he talks, swallowing his words. His nervousness is understandable - it is illegal in Zambia for men to have sex with each other, and socially unacceptable. A survey of prisoners in 1998 suggested that 27% were HIV-positive - eight points higher than the national rate at the time. The organisation which carried out the research, In But Free, is updating its figures but is anticipating a similar discrepancy. Many men will already be carrying the virus when they are imprisoned, but once inside it can be spread by tattooing and sharing razors. The biggest risk factor, though, is sex.

Despite his sometimes ambiguous attitude, President Jacob Zuma has been tested for HIV and his government's policy has improved
     Even though South Africa has more people infected with HIV than any other country in the world, candid discussion of the virus is still a taboo for many. But when President Jacob Zuma launched a campaign on April 25th to get more people to have themselves tested, he had no qualms. He himself had recently taken a test in front of the cameras (above). Though it was said at first that the results would not be disclosed, Mr Zuma told his audience that his sample, like three previous ones, had "registered a negative outcome for the HI virus". This drew strong applause.
     It was good news for Mr Zuma. Seeing that less than 20% of South Africans know whether they have HIV or not, it may also have helped to lessen the stigma that afflicts people with AIDS and hampers efforts to tackle the epidemic.
     But Mr Zuma's candour may have sent a less useful signal too. He has at least 20 children by at least eight different women. At his trial in 2006 for rape (for which he was acquitted) he admitted having unprotected sex with a woman he knew to be HIV-positive, saying he took a shower afterwards to fend off the virus. Although he may have encouraged people to take HIV tests, some may take Mr Zuma's negative result to imply that his risky behaviour was not so foolish after all.

Ever since the AIDS problem was discovered nearly 30 years ago, the deadly acquired immune deficiency syndrome remains a challenge to the society. Now, it is important that we base our initiatives on some understanding of what has gone wrong. Unfortunately and in many ways, the world, countries and communities have struggled to overcome social and economic challenges posed by HIV/AIDS.
     Though there is much campaign and struggle to fight HIV/AIDS, the seemingly unstoppable, disaster and catastrophic human tragedy caused by the disease continues in some parts of the world. It should be noted that some factors contribute to the failure of success against HIV/AIDS. To some extent silence and denial are a primordial and protective human response to situations that are excessively stressful.
     It's true that human kind cannot bear too much reality, but trying to cover up the existence of AIDS will never lead to mastery over the disease or its impacts. This habit still commonly occurs in families, communities, and in several parts of the world. Attitudes, behaviors, insidious associations, and adverse social reactions that discriminate against and stigmatize those with HIV/AIDS drive acknowledgement of the disease into an underground of silence, secrecy, shame and self recrimination. Lack of correct information on how the disease can be contracted, how it can be prevented, and what those infected can do to ensure that they live a longer life of better quality still remains a challenge.
     Today a significant proportion of people do not know how to be protected against HIV infection. Some even do not know that oral and anal sex involve extensive HIV transmission risks. People still think that you can judge by appearances whether or not a person is HIV infected.

She is HIV positive, pregnant and has lived without drugs for nine years. And scientists are watching her with keen interest because the virus in her body is undetectable. The patient, who cannot be named for confidentiality, is now four months pregnant and doctors want to see if she can deliver a HIV-negative baby without using ARVs or Caesarean Section, the key interventions used to significantly cut-down chances of a mother transmitting the virus to her baby.
     "We are doing CD4 and viral load tests in close frequencies to establish how they are before we decide how she will deliver," says Dr Surendra Patel, an expert in infectious diseases at MP Shah Hospital. "If the viral load remains undetectable, then there will be no justification to intervene with ARVs or Caesarean Section during birth."
     Her CD4 count - immune cells used to fight infections - is 1,200 and the viral load is below 40 copies/mL, the level at which the virus is defined as undetectable. CD4 count for an HIV-negative healthy individual is over 410. The woman is one of the seven other HIV-positives who have kept the virus at undetectable levels many years after being infected.
     A similar phenomenon is being studied by scientists at the Kenya Aids Vaccine Initiative, where out of the more than 200 people they have kept tabs on for several years, three may hold the key to a broadly neutralising antibody vaccine. "So far, we have isolated a few individuals who have very promising results and now they are being studied to understand how their immune system is able to neutralise the virus," says Prof Omu Anzala, virologist and Kavi director.
     This phenomenon is evident in men and women who have been screened in Nairobi. Dr Patel has monitored his patients for over five years to establish what makes them tick. They have neither used any anti-retroviral drugs nor been attacked by opportunistic infections despite living with the virus. Of the eight people, one has CD4 count of 1,800, with the viral load below 40 copies or undetectable level.
     "In the next 18 months, we hope to complete the follow-up and issue a statement on our findings," Dr Patel says. These cases are what have come to be known as the Elite Controllers - people whose immune system is able to control the HIV viral load to less than 40 copies/mL compared to over 30,000 copies/mL of HIV in a person without such antibodies.

A stochastic spatial model based on the Monte Carlo approach is developed to study the dynamics of human immunodeficiency virus (HIV) infection. We aim to propose a more detailed and realistic simulation frame by incorporating many important features of HIV dynamics, which include infections, replications and mutations of viruses, antigen recognitions, activations and proliferations of lymphocytes, and diffusions, encounters and interactions of virions and lymphocytes. Our model successfully reproduces the three-phase pattern observed in HIV infection, and the simulation results for the time distribution from infection to AIDS onset are also in good agreement with the clinical data. The interactions of viruses and the immune system in all the three phases are investigated. We assess the relative importance of various immune system components in the acute phase. The dynamics of how the two important factors, namely the viral diversity and the asymmetric battle between HIV and the immune system, result in AIDS are investigated in detail with the model.

     Background Adult deaths are a crucial priority for global health. Causes of adult death are important components of Millennium Development Goals 5 and 6. However, adult mortality has received little policy attention, resources, or monitoring efforts. This study aimed to estimate worldwide mortality in men and women aged 15-59 years.
     Methods We compiled a database of 3889 measurements of adult mortality for 187 countries from 1970 to 2010 using vital registration data and census and survey data for deaths in the household corrected for completeness, and sibling history data from surveys corrected for survival bias. We used Gaussian process regression to generate yearly estimates of the probability of death between the ages of 15 years and 60 years (45q15) for men and women for every country with uncertainty intervals that indicate sampling and non-sampling error. We showed that these analytical methods have good predictive validity for countries with missing data.
     Findings Adult mortality varied substantially across countries and over time. In 2010, the countries with the lowest risk of mortality for men and women are Iceland and Cyprus, respectively. In Iceland, male 45q15 is 65 (uncertainty interval 61-69) per 1000; in Cyprus, female 45q15 is 38 (36-41) per 1000. Highest risk of mortality in 2010 is seen in Swaziland for men (45q15 of 765 [692-845] per 1000) and Zambia for women (606 [518-708] per 1000). Between 1970 and 2010, substantial increases in adult mortality occurred in sub-Saharan Africa because of the HIV epidemic and in countries in or related to the former Soviet Union. Other regional trends were also seen, such as stagnation in the decline of adult mortality for large countries in southeast Asia and a striking decline in female mortality in south Asia.
     Interpretation The prevention of premature adult death is just as important for global health policy as the improvement of child survival. Routine monitoring of adult mortality should be given much greater emphasis.
     Funding Bill & Melinda Gates Foundation.

Even as another AIDS Vaccine Day (May 18) is in sight, the fervent search for a HIV vaccine has given way to silent, but diligent research. Kalyan Ray spoke to Wayne C Koff, chief scientific officer of New York-based International AIDS Vaccine Initiative on the ups and downs in AIDS research.  

Research on AIDS vaccines is over a decade old. Why are there so few successes?
Scientific advances are often incremental and vaccine development in particular has typically been a decades-long affair. The polio vaccine was developed 47 years after the virus was identified. The vaccine has had several successes over the past year alone, including among other things, the first demonstration in humans that an AIDS vaccine can in fact prevent HIV infection and the discovery of new antibodies that potently neutralise a broad range of HIV variants - and whose characterisation has revealed new vulnerabilities on the virus for vaccine designers to target. 

The HIV virus is smart. But how can a tiny virus become so smart as to fox scores of scientists worldwide?
It is quite simply the most elusive virus scientists have ever come across. There are several reasons for this. First, HIV is - far and away - the most mutable pathogen known to modern medicine, one that changes rapidly and constantly over the course of an infected person's life. Every time the immune system of an infected person figures out how to target the virus, it simply mutates and avoids detection. Vaccine designers hoping to teach the body how to detect and destroy HIV are similarly challenged by its mutability.
     Second, HIV very quickly inserts itself into the genetic makeup of human cells - hiding out in human DNA, far from the reach of the immune response, to sporadically re-emerge over the course of an infected person's life. Third, the virus has evolved several other equally cunning mechanisms to evade neutralisation.
     Finally, it attacks the very cells the immune system - and any vaccine - would need to marshal to clear the body of infection. Simply put, HIV is a formidable foe and will not be easily conquered. Still, scientists have developed vaccines against variable pathogens for which no ideal animal models exist - as is the case for HIV. A number of lines of evidence from both human and animal studies suggest that vaccines can be made to prevent HIV infection.

Why do we need vaccines in the first place because prevention programmes can bring down the prevalence of the disease and medicines are available to treat the infected persons?
Existing prevention programmes are valuable components to the AIDS crisis. Any vaccination campaign would complement but never entirely replace them. Still, these programmes have proved to be limited by their dependence on the willingness of people to modify their behaviour and make risk-reducing practices a habit. Condoms only work if used, and if partners agree to their use. Similarly, drugs are effective only if taken properly. They are also costly over the long term. Today, for every two people who receive life-saving anti-retroviral treatment, another five are newly infected with HIV.

With HIV infection rates on the rise, Torrance-area researchers will begin a national study looking at the safety of a microbicide gel they hope can be used by women to protect themselves against infection. Los Angeles Biomedical Research Institute was selected as one of five test sites by a South African organization, the International Partnership for Microbicides, seeking alternatives for women whose partners won't use a condom.
     "Partners don't always want to cooperate," said Dr. Susan Ballagh, the local researcher who will be conducting the study. "We're hoping this gel will be used once a day, like the (birth control pill) now to prevent pregnancy, to ward off infection."
     There are currently no federally approved microbicides for the prevention of HIV and AIDS. Dozens of products - which also come in the form of creams, suppositories, films, lubricants and sponges - have failed in various stages of clinical trials. Some of the trials were halted due to safety concerns; others failed to show any difference in infection rates among women who used the gel and those in a placebo group.
     Most of the efficacy trials are conducted in Africa, where infection rates are extremely high. The trial taking place in Torrance will only test the safety of a new product, called dapivirine. Despite past failures, researchers are hopeful this product will pass muster.

An International multi-centre study was conducted to assess the performance of a panel of simian immunodeficiency virus (SIV) RNA reference materials for plasma viral load determinations. Reliable quantification was demonstrated across 6 log10 dynamic range. Availability of external reference materials will enable independent calibration of SIV plasma viral load assays.

Zimbabwe needs to circumcise 1,2 million men by 2015 if the male circumcision intervention against the spread of HIV is to have a national impact, a senior Health and Child Welfare Ministry official has said. Under the pilot circumcision programme that started in 2007, over 5 000 men have been circumcised.
     Addressing a two-day workshop on the male circumcision rollout strategy last week, head of the ministry's Aids Tuberculosis Unit Dr Owen Mugurungi said there was need to circumcise a critical mass. Male circumcision reduces chances of contracting HIV by 60 percent. It must be complemented by condom use, abstinence and faithfulness to one partner.
     "MC is not vaccination. It only makes a difference if only done on a critical mass," he said. There is no direct advantage in circumcising HIV positive males, the workshop heard. Dr Mugurungi said: "If we continue without MC, 95 000 men will be infected each year. "If we do MC, less than 20 000 will be infected," he said.
     MC focal person in the Health Ministry Dr Sinokuthemba Xaba said emphasis should be on circumcising the 15 to 29-year age group, as it was the most affected by HIV and Aids. "We need impact today," he said.
     Workshop participants advocated for more resources and payment of incentives to health personnel performing the procedure following reports that some centres had closed because of lack of funding. The workshop drew participants from the Health Ministry, district and provincial hospitals, NGOs, the private sector and the Zimbabwe Union of Journalists.

Collins went to Capitol Hill today to express his support for President Barack Obama's proposed 2011 budget for the institutes. Collins told the House Committee on Appropriations' Subcommittee on Labor, Health, and Human Services that NIH plans to use the proposed $32.2 billion in funding next year to push the edges of biomedical research, to support the next-generation of young scientists, and to continue making the kinds of discoveries that have made American lifespans dramatically longer in recent decades.
     Collins pointed the committee toward NIH research in genomics, personalized medicine, and stem cells research as some of the approaches the institutes are using to pursue knowledge about, and treatments for, a number of diseases. He also echoed the remarks of his predecessor, Elias Zerhouni, who said that biomedical research is "a race that we cannot afford to lose."
     But, he added, "Science is not a 100-yard dash. "It is a marathon ­ a marathon run by a relay team that includes researchers, patients, industry experts, lawmakers, and the public." "Although we have accomplished much, and as tempting as it may be for NIH to rest upon its laurels, we all know that biomedical research still has an enormous amount of ground to cover before discovery is turned into health for all Americans," Collins said, adding that more than one person in the US dies every minute from cancer.
     Collins told the subcommittee, which is chaired by Dave Obey (D ­ Wis.), that when he arrived at NIH in 2009 he surveyed anew the agency where he had already spent 15 years directing its genomics efforts. "I found many of the most exciting opportunities could be grouped under five main themes: taking greater advantage of high-throughput technologies; accelerating translational science, that is, turning discovery into health; helping to reinvent health care; focusing more on global health; and reinvigorating the biomedical research community," he said.

Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals ('elite controllers') maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.

For those of you who, like me, wonder why the cost of getting a drug to market continues to grow each year, here's what may be a piece of the puzzle: It's getting harder to do clinical studies. A report released this morning by the Tufts Center for the Study of Drug Development describes how clinical trials are getting more complex and harder to execute, and how it's becoming more difficult to recruit and retain patients in these studies.
     The report is a follow-up to a 2007 analysis performed by the center. The study looked at over 8,000 protocols from more than 75 pharmaceutical and biotechnology companies. The report found, among other things, that the median number of procedures in a clinical trial increased by 49 percent, comparing the period of 2000-2003 with 2004-2007. Reflecting the rising complexity of trials, the number of eligibility criteria for entering patients into a study grew by 58 percent over that time, causing fewer patients to enroll in trials (enrollment rates fell 21 percent). Not only that, but it was harder to keep patients in studies because of the large number of procedures, the report said.
     The Tufts researchers also found that between 2002 and 2007 trials in oncology, immunology, and central nervous systems indications saw the biggest rise in procedures per trial. Kenneth Kaitin, director of the center, says the increasing complexity comes from a number of factors, chief among them that the types of products being developed today tend to be geared towards more chronic and challenging indications. "Therefore the trials tend to be more complex," he says.
     The report, however, did not correlate the rise in complexity with any cost figures. How much does an average phase II trial cost today compared to, say, five years ago? How have the costs of a phase III or phase IV study changed? Dr. Kaitin says that as far as he knows there are no studies out there with those kinds of figures. There is an explanation, though: Companies are not very eager to share these numbers. Still, he says he strongly believes the overall increase in complexity goes hand in hand with higher costs.

We have shown that following priming with replicating adenovirus type 5 host range mutant (Ad5hr)-HIV/SIV recombinants, boosting with gp140 envelope protein enhances acute phase protection against intravenous SHIV89.6P challenge compared to priming and no boosting or boosting with an HIV polypeptide representing the CD4 binding site of gp120. We retrospectively analyzed antibodies in sera and rectal secretions of these same macaques, investigating the hypothesis that vaccine-elicited non-neutralizing antibodies contributed to the better protection. Compared to other immunized groups or controls, the gp140-boosted group exhibited significantly greater antibody activities mediating antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated viral inhibition (ADCVI) in sera, and transcytosis inhibition in rectal secretions. ADCC and ADCVI activities were directly correlated with antibody avidity, suggesting the importance of antibody maturation for functionality. Both ADCVI and % ADCC killing pre-challenge were significantly correlated with reduced acute viremia. The latter as well as post-challenge ADCVI and ADCC were also significantly correlated with reduced chronic viremia. We have previously demonstrated induction by the prime/boost regimen of mucosal antibodies that inhibit transcytosis of SIV across an intact epithelial cell layer. Here, antibody in rectal secretions was significantly correlated with transcytosis inhibition. Importantly, the transcytosis specific activity (% inhibition/total secretory IgA and IgG) was strongly correlated with reduced chronic viremia suggesting that mucosal antibody may help control cell-to-cell viral spread during the course of infection. Overall, the replicating Ad5hr-HIV/SIV priming/gp140 protein boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities associated with control of both acute and chronic viremia.

     Objectives To determine the safety of 0.5% and 2% PRO 2000 gel in terms of local and systemic adverse events (AE) and the acceptability of gel use.
     Design A randomised placebo-controlled trial among healthy, sexually active African women aged 18-45 years. Between June 2003 and September 2004, 180 consenting women were randomly assigned to one of four groups: PRO 2000 gel (0.5% or 2%), placebo gel, or condom use only. Participants were screened for sexually transmitted infections, with HIV counselling and testing. Women randomly assigned to gel used this intravaginally twice a day for 28 days. Follow-up visits were fortnightly up to 6 weeks from enrolment, and comprised a physical examination including colposcopy, laboratory testing and questionnaire interviews. 
     Results Ten women were lost to follow-up, none due to AE. Adherence with total gel doses was 69%. Observed rates of the primary toxicity endpoints, ulceration greater than 2x1 cm and clinically relevant coagulation abnormalities were, for PRO 2000 0.5%: 1.6% (95% CI 0.04% to 8.5%) and 0% (97.5% CI 0% to 5.7%), and for PRO 2000 2%: 0% and 0% (97.5% CI 0% to 5.9%). Women randomly assigned to active gels did not show an increased rate of AE. Gel use had no significant effect on haematology and biochemistry results. Women found gel use highly acceptable.
     Conclusions Both concentrations of PRO 2000 gel were found to be safe and well tolerated. These data justified testing the gels in large-scale effectiveness trials.

The low number of new drugs reaching the market in recent years is a concern for public health and for the drug development enterprise. A high failure rate of clinical development programmes has been identified as a major cause for the pharmaceutical productivity gap[1], but regulatory approval rates may also have a role.

Researchers in China have created what they claim is the most "detailed and realistic" model of HIV to date, and say that it could help in the creation of a vaccine for the deadly virus. However, immunologists warn that the model is yet to catch up with modern clinical trials.
     According to the World Health Organization, HIV is one of the world's biggest health challenges, infecting almost three million people and killing some two million people every year. When a person is infected, HIV enters into the immune system's crucial T lymphocytes - or T cells - and replicates itself by integrating with the DNA. As a result the cells die and the immune system slowly weakens until it can no longer fight off opportunistic infections, a status classified as AIDS.
     The scale of the AIDS epidemic has prompted many scientists to search for an HIV vaccine, but this has proved difficult. HIV is different from other viruses in that it can mutate very quickly, thereby evading the normal immune-system defences. Some scientists think that a vaccine will only become available once there is a leap in the theoretical understanding of the virus.

To view the study, click here.

Senior United Nations officials on a joint mission to Mali have lauded the country for its progress in expanding HIV prevention, treatment, care and support, stating it can serve as an example to the rest of the continent in tackling the epidemic.
     "From what I have read, the strategies in Mali are among the most successful of any country on the continent," said Helen Clark, the Administrator of the UN Development Programme (UNDP). "I am sure many are interested to learn from your experience."
     Miss Clark is on a four-day visit to Mali, along with Michel Sidibe, the Executive Director of the Joint UN Programme on HIV/AIDS (UNAIDS). They began their visit in the city of Timbuktu, where they visited Groupe d'Appui a la Formation de Base (GAFB), a local civil society organization that provides HIV prevention through innovative peer education programmes among vulnerable populations, including uniformed services, youth, and domestic workers.
     "Twenty years ago when I was Minister of Health in my own county, we had the same chance that you have today in this region to stop the epidemic in its tracks," said Miss Clark, a native of New Zealand. "We were successful because we had a very inclusive approach. "Mali should be the example for other countries in Africa on how to halt the HIV epidemic," she added.

The development of alternative strategies to prevent HIV infection is a global public health priority. Initial efforts in anti-HIV microbicide development have met with poor success as the strategies have relied on a non-specific mechanism of action. Here, we report the development of a microbicide aimed at specifically blocking HIV entry by displaying molecular components of the HIV/host cell attachment complex on the surface of Caulobacter crescentus, a harmless aquatic bacterium. This bacterium can be readily manipulated to present heterologous proteins at high density on its surface by genetic insertion into its crystalline surface layer protein [1], [2]. In separate constructions, we generated bacteria displaying domain 1 of CD4 and MIP1a[alpha]. Each moiety reacted with specific antibodies by Western immunoblot and immuno-fluorescence microscopy. Microbicide functionality was assessed using an HIV pseudotype virus assay system representing Clade B subtypes. Bacteria displaying MIP1a[alpha] reduced infectivity by 35-78% depending on the specific subtype while CD4 display reduced infection by as much as 56%. Combinations of both constructs reduced infectivity by nearly 98%. We demonstrated that HIV infection could be inhibited using a strategy aimed at HIV-specific molecular interactions with Caulobacter surface protein display, and that sufficient protein folding and conformation could be mimicked to bind and block entry. Further, this is the first demonstration that Caulobacter surface protein display may be a useful approach to preventing HIV infection or other viruses as a microbicide. We propose that this harmless bacterium, which is inexpensive to produce and formulate, might be suitable for topical applications as a viable alternative in the search for effective microbicides to counteract the world wide incidence of HIV infection.

Worldwide HIV infects women more frequently than men, and it is clear that not all exposed to HIV become infected. Several populations of HIV-exposed uninfected (EU) women have been identified, including discordant couples and sex workers. Understanding what provides natural protection in EU women is critical in vaccine or microbicide development. However, correlates of protection in these women are still unclear. Most studies have used classical methods, examining single genes or cellular factors, a mainstay for traditional immunobiology. This reductionist approach may be limited in the information it can provide. Novel technologies are now available that allow us to take a "systems biology" approach, which allows the study of a complex biological system and identifies factors that may provide protection against HIV infection. Herein we report developments in discovery-based systems biology approaches in EU women and how this broadens our understanding of natural protection against HIV-1.

As new pharmaceutical products to combat the acquisition of HIV are produced, their clinical efficacy is determined through large-scale clinical trials. Trial participants, however, also independently evaluate the effectiveness of these technologies. During a phase III microbicide clinical trial in Johannesburg, South Africa, female participants acknowledged that although the gel had not yet been clinically proven to be efficacious, they believed that it was capable of healing infections, cleansing the vagina, increasing fertility, and preventing HIV. These responses were informed by experiences of gel use coupled with ideas regarding the flow of bodily fluids and the removal of dirt for bodily cleanliness and the maintenance of health. Examining participant responses to the gel provides insight into the relationship between knowledge and experience when utilizing previously unfamiliar biotechnologies.

     Background Previous studies have shown that 3-hydroxyphthalic anhydride (HP)-modified bovine milk protein, beta-lactoglobulin (beta-LG), is a promising microbicide candidate. However, concerns regarding the potential risk of prion contamination in bovine products and carcinogenic potential of phthalate derivatives were raised. Here we sought to replace bovine protein with an animal protein of non-bovine origin and substitute HP with another anhydride for the development of anti-HIV microbicide for preventing HIV sexual transmission.
     Results Maleic anhydride (ML), succinic anhydride (SU) and HP at different conditions and variable pH values were used for modification of proteins. All the anhydrate-modified globulin-like proteins showed potent anti-HIV activity, which is correlated with the percentage of modified lysine and arginine residues in the modified protein. We selected maleic anhydride-modified ovalbumin (ML-OVA) for further study because OVA is easier to obtain than beta-LG, and ML is safer than HP. Furthermore, ML-OVA exhibited broad antiviral activities against HIV-1, HIV-2, SHIV and SIV. This modified protein has no or low in vitro cytotoxicity to human T cells and vaginal epithelial cells. It is resistant to trypsin hydrolysis, possibly because the lysine and arginine residues in OVA are modified by ML. Mechanism studies suggest that ML-OVA inhibits HIV-1 entry by targeting gp120 on HIV-1 virions and also the CD4 receptor on the host cells.
     Conclusion ML-OVA is a potent HIV fusion/entry inhibitor with the potential to be developed as an effective, safe and inexpensive anti-HIV microbicide.

     Background: Analysis of HIV transmission rates has provided insight into the impacts of HIV-related prevention programing and policies in the United States by providing timely information beyond incidence or prevalence alone. The purpose of this analysis is to use transmission rates to assess past prevention efforts and explore trends of the epidemic in subpopulations within Thailand.
     Methods: Asian Epidemic Model HIV incidence and prevalence were used to calculate transmission rates over time nationally and among high-risk populations.
Results: A national HIV/AIDS program implemented in Thailand in the 1990s that targeted sex workers and the general population was correlated with a decrease in new cases despite high prevalence. The turning point of the epidemic was in 1991 when the national transmission rate was 32%. By the late 1990s, the rate dropped to less than 4%. All subpopulations experienced a rate decline; however, sex workers still experienced higher transmission rates.
     Conclusions: The declining trend in HIV transmission rates despite ever-growing prevalence indicates prevention success correlated with the national HIV/AIDS program. Data from subgroup analyses provide stronger evidence of prevention success than incidence alone, as this measure demonstrates the effect of efforts and accounts for the burden of disease in the population.

     Background South Africa, with its scientific capacity, good infrastructure and high HIV incidence rates, is ideally positioned to conduct large-scale HIV prevention trials. The HIV Prevention Research Unit of the South African Medical Research Council conducted four phase III and one phase IIb trials of women-initiated HIV prevention options in KwaZulu-Natal between 2003 and 2009. A total of 7046 women participated, with HIV prevalence between 25% and 45% and HIV incidence ranging from 4.5-9.1% per year. Unfortunately none of the interventions tested had any impact on reducing the risk of HIV acquisition; however, extremely valuable experience was gained, lessons learned and capacity built, while the communities gained associated benefits.
     Experience Our experience in conducting these trials ranged from setting up community partnerships to developing clinical research sites and dissemination of trial results. Community engagement included setting up community-based research sites with approval from both political and traditional leaders, and developing community advisory groups to assist with the research process. Community-wide education on HIV/sexually transmitted infection prevention, treatment and care was provided to over 90 000 individuals. Myths and misconceptions were addressed through methods such as anonymous suggestion boxes in clinic waiting areas and intensive education and counselling. Attempts were made to involve male partners to foster support and facilitate recruitment of women. Peer educator programmes were initiated to provide ongoing education and also to facilitate recruitment of women to the trials. Recruitment strategies such as door-to-door recruitment and community group meetings were initiated. Over 90% of women enrolled were retained. Community benefits from the trial included education on HIV prevention, treatment and care and provision of ancillary care (such as Pap smears, reproductive health care and referral for chronic illnesses). Social benefits included training of home-based caregivers and sustainable ongoing HIV prevention education through peer educator programmes. Challenges Several challenges were encountered, including manipulation by participants of their eligibility criteria in order to enroll in the trial. Women attempted to co-enroll in multiple trials to benefit from financial reimbursements and individualised care. The trials became ethically challenging when participants refused to take up referrals for care due to stigma, denial of their HIV status and inadequate health infrastructure. Lack of disclosure of HIV status to partners and family members was particularly challenging. Some of the ethical dilemmas put to the test our responsibility as researchers and our obligation to provide health care to research participants.
     Conclusion Conducting these five trials in a period of six years provided us with invaluable insights into trial implementation, community participation, recruitment and retention, provision of care and dissemination of trial results. The critical mass of scientists trained as clinical trialists will continue to address the relentless HIV epidemic in our setting and ensure our commitment to finding a biomedical HIV prevention option for women in the future.

     Background Medical male circumcision is now part of a comprehensive approach to HIV prevention. It has been shown that awareness of the protective effect of male circumcision leads to high acceptability towards the introduction of medical male circumcision services within countries. The objective of this survey was to identify factors determining awareness of male circumcision for HIV prevention.
     Methods We interviewed 452 participants (267 adults >24 years of age; 185 youths 14-24 years) living in three rural Ugandan districts in 2008. Using a standardized questionnaire, we assessed socio-demographic parameters, awareness of MC for HIV prevention, general beliefs/attitudes regarding MC and MC status. Determinants for awareness of MC for HIV prevention were examined with multiple logistic regression models.
     Results Out of all adults, 52.1% were male (mean+/-SD age 39.8+/-11 years), of whom 39.1% reported to be circumcised. Out of all youths, 58.4% were male (18.4+/-2.5), 35.0% circumcised. Adults were more aware of MC for HIV prevention than youths (87.1% vs. 76.5%; p=0.004). In adults, awareness was increased with higher educational level compared to no school: primary school (adjusted OR 9.32; 95%CI 1.80-48.11), secondary (5.04; 1.01-25.25), tertiary (9.91; 0.76-129.18), university education (8.03; 0.59-109.95). Younger age and male sex were further significant determinants of increased awareness, but not marital status, religion, district, ethnicity, employment status, and circumcision status. In youths, we found a borderline statistically significant decrease of awareness of MC for HIV prevention with higher educational level, but not with any other socio-demographic factors.
     Conclusions Particularly Ugandans with low education, youths, and women, playing an important role in decision-making of MC for their partners and sons, should be increasingly targeted by information campaigns about positive health effects of MC.

In the absence of a vaccine, there is an urgent need for the development of safe and effective topical microbicides to prevent the sexual transmission of HIV-1. In this study, we proposed to develop a novel class of microbicides using syndecan as the antiviral agent. Specifically, we generated a soluble syndecan-Fc hybrid molecule by fusing the ectodomain of syndecan-1 to the Fc domain of a human IgG. We then tested the syndecan-Fc hybrid molecule for various in vitro microbicidal anti-HIV-1 properties. Remarkably, the syndecan-Fc hybrid molecule possesses multiple attractive microbicidal properties: it i) blocks HIV-1 infection of primary targets including T cells, macrophages and DC; ii) exhibits a broad range of antiviral activity against primary HIV-1 isolates, multi-drug resistant HIV-1 isolates, HIV-2 and SIV; iii) prevents transmigration of HIV-1 through human primary genital epithelial cells; iv) prevents HIV-1 transfer from dendritic cells to CD4+ T cells; v) is potent when added 2 h prior to addition of HIV-1 to target cells; vi) is potent at a low pH; vii) blocks HIV-1 infectivity when diluted in genital fluids; and viii) prevents herpes simplex virus infection. The heparan sulfate chains of the syndecan-Fc hybrid molecule are absolutely required for HIV-1 neutralization. Several lines of evidence suggest that the highly conserved Arg298 in the V3 region of gp120 serves as the locus for the syndecan-Fc hybrid molecule neutralization. In conclusion, this study suggests that the syndecan-Fc hybrid molecule represents the prototype of a new generation of microbicidal agents that may have promise for HIV-1 prevention.

Democratic Sens. Tom Harkin of Iowa and Arlen Specter of Pennsylvania, who traded the chairman's gavel of the Labor-HHS-Education Appropriations Subcommittee over many years, have worked plenty of magic when it comes toboosting the budget of the National Institutes of Health. But comments by Harkin after a hearing by the panel Wednesday suggested that the magic maybe fading.
     "I don't have a magic pot I can go to," he said when asked about Specter's insistence during the hearing that a bigger increase for NIH could be found than the $1 billion hike sought by the Obama administration.
     NIH Director Francis S. Collins used the hearing to show off to the appropriators some of the shiniest pearls of research under way at the National Institutes, which Specter lauded as the "crown jewels," and maybe the only crown jewels, of the federal government.
     Perhaps hinting at a budget increase higher than Obama wants, Collins said,"If our nation can be bold enough to act upon these many unprecedented opportunities, we'll be amazed at what tomorrow will bring and how swiftly we can turn discovery into health."
     Harkin was perhaps more impressed than anyone, posing dozens of questions to Collins about various programs and occasionally expressing amazement at the projects, including a big study of a vaccine that may help smokers quit by turning off tobacco's ability to trigger a pleasure response in the brain.
     But Harkin expressed skepticism about coming up with a lot of added funding for NIH next year, even after Specter repeatedly insisted that it was possible. 

To the Editor: The findings of Celum et al. (Feb. 4 issue)[1] add to the disappointing outcomes of trials investigating whether treatment of sexually transmitted infections reduces transmission of the human immunodeficiency virus type 1 (HIV-1). Despite this intervention failure, the subgroup analysis by Celum et al. (Figure 4 of their article) indicates that the incidence of HIV-1 infection among persons who were seropositive for herpes simplex virus type 2 (HSV-2) was approximately double the incidence among persons who were seronegative for HSV-2. This finding suggests that HSV-2 may be more important in the acquisition of HIV-1 in susceptible people than the infectiousness of persons with HIV-1 infection.
     According to other studies, the reduction in the plasma viral load of 0.25 log10 copies per milliliter in persons treated for HSV-2 would be expected to result in a 20% reduction in rates of HIV-1 transmission per sexual act.2,3,4 However, over many sexual exposures, the observed effectiveness would be greatly reduced.5 These findings are consistent with the results of Celum and colleagues in that differences in incidence rates in the two study groups diminished over time (Figure 3 of their article). Thus, the treatment of sexually transmitted infections to reduce HIV-1 transmission may provide a modest benefit in people with limited HIV-1 risk exposure. Available evidence, including the valuable study by Celum et al., suggests that other strategies are required to mitigate HIV-1 epidemics.

Additional correspondence on this topic, including a letter by Ruark, Shelton, and Halperin and a reply by the study authors, is available in the 6 May issue of NEJM. To read the original study, click here.

A computer model proposes a solution to a long-standing mystery in HIV research - why a small percentage of people infected with the virus never develop full-blown AIDS. The answer lies in how the immune cells that recognize invaders are educated, and suggests new strategies for designing an HIV vaccine.
     The human immune system detects foreign cells with the help of cell-surface proteins called human leukocyte antigens (HLAs). Each person's cells carry a particular set of HLA molecules - the person's HLA type - which bind fragments of virus or bacterial protein and 'present' them to T cells, the immune cells that recognize and attack infected cells. But before T cells are ready to perform their killer function, they are in effect trained on fragments of the body's own proteins - self-peptides - in an organ called the thymus. To 'graduate' from the thymus, a T cell must be able to recognize at least one combination of HLA molecule and self-peptide, which provides the template for its subsequent immune response against a foreign peptide bound to that HLA molecule. T cells that bind to self-peptides very strongly, however, are rejected, as they would attack the body's own cells.

To read the study, click here.

PAR-10-184, NIAID Clinical Trial Implementation Grant (R01)
PAR-10-185, NIAID Clinical Trial Planning Grant (R34)
PAR-10-186, NIAID Clinical Trial Implementation Cooperative Agreement (U01) 

     Purpose. The purpose of this Funding Opportunity Announcement (FOA) issued by the National Institute of Allergy and Infectious Diseases (NIAID) is to invite applications that propose implementation of investigator-initiated non-high-risk clinical trials.  The trials must be hypothesis-driven, related to the research mission of the NIAID and considered a high priority by the Institute.  Investigators are encouraged to visit the NIAID website for additional information about the research mission and high-priority research areas of the NIAID http://www3.niaid.nih.gov/about/whoWeAre/planningPriorities/.)  Only one clinical trial may be proposed in each NIAID Clinical Trial Implementation (R01) Grant application.
     This FOA will utilize the NIH research project (R01) award mechanism, and runs in parallel with two related FOAs, PAR-10-185 and PAR-10-186, that invite applications for NIAID Clinical Trial Planning (R34) Grants, which support planning activities for investigator-initiated clinical trials, and  NIAID Clinical Trial Implementation (U01) Cooperative Agreements, which  support implementation of investigator-initiated, high-risk clinical trials, respectively.
     Mechanism of Support. This FOA will utilize the NIH research project (R01) award mechanism and runs in parallel with two related FOAs, PAR-10-185 and PAR-10-186, that invite applications that propose planning of investigator-initiated clinical trials and implementation of high-risk investigator-initiated clinical trials, respectively.  Pre-approval by the NIAID is required for submission of an application under all three FOAs.
     Funds Available and Anticipated Number of Awards. The total amount awarded and the number of awards will depend upon the numbers, quality, duration, and costs of the applications received.