30 APRIL 2010, VOLUME 11, ISSUE 14

The search for an HIV/AIDS vaccine is steadily moving ahead, generating and validating new concepts in terms of novel vectors for antigen delivery and presentation, new vaccine and adjuvant strategies, alternative approaches to design HIV-1 antigens for eliciting protective cross-neutralising antibodies, and identification of key mechanisms in HIV infection and modulation of the immune system. All these different perspectives are contributing to the unprecedented challenge of developing a protective HIV-1 vaccine. The high scientific value of this massive effort is its great impact on vaccinology as a whole, providing invaluable scientific information for the current and future development of new preventive vaccine as well as therapeutic knowledge-based infectious-disease and cancer vaccines.

Letter
The News of the Week story "Elsevier to editor: Change controversial journal or resign" (M. Enserink, 12 March, p. 1316) reports on the withdrawal of a controversial HIV paper from Medical Hypotheses, a journal published by Elsevier. The paper in question claimed to refute the pivotal results of the National Heart, Lung, and Blood Institute Transfusion Safety Study, which revealed that 111 of 124 (89.5%) recipients of a single unit of HIV-infected blood became infected and that the rate of progression to AIDS within the first 38 months after infection was similar to that reported for homosexual men (1). Given such compelling data in support of HIV as the etiologic agent of AIDS, published in a prestigious medical journal, it was strange that Duesberg and Rasnick (2) put forth their hypothesis in 1998 that HIV does not cause AIDS. Propaganda exemplified by Duesberg's first and subsequent papers on the subject, and coupled with information freely disseminated through the Internet (e.g., http://en.wikipedia.org/wiki/AIDS_denialism), has indeed distracted from confronting AIDS in South Africa. Elsevier's due diligence in a responsible withdrawal of Duesberg's recent paper from Medical Hypotheses is commendable and will hopefully put an end to perpetuation of a dogma that is damaging to science and society. Only an effective HIV vaccine can ultimately end this drama.

Vaginal mucosal microflora are typically dominated by Gram positive Lactobacillus species, and colonization of vaginal mucosa by exogenous microbicide-secreting Lactobacillus strains has been proposed as a means of enhancing this natural mucosal barrier against human immunodeficiency virus (HIV) infection. We asked whether an alternative strategy could be utilized whereby anti-HIV molecules are expressed within the cervico-vaginal milieu by endogenous vaginal Lactobacillus populations, which have been 'engineered' in situ via transduction. In this study, we therefore investigated the feasibility of utilizing transduction for the expression of the HIV co-receptor antagonists, the CC-chemokines CCL5 and CCL3 in a predominant vaginal Lactobacillus species, Lactobacillus gasseri. Modifying a previously established transduction model, which utilizes Lactobacillus gasseri ADH and its prophage adh, we show that mitomycin C induction of L. gasseri ADH transformants containing pGK12-based plasmids, with CCL5 and CCL3 expression and secretion cassettes (under the control of promoters P6 and P59, respectively), and a 232 bp adh cos-site fragment, results in the production of transducing particles which contain 8-9 copies of concatameric plasmid DNA. High frequency transduction was observed for these particles (almost 6 orders of magnitude greater than that of pGK12 alone) and transductants were found to contain re-circularized expression plasmids with subsequent culture. Importantly, transductants produced CC-chemokines at levels comparable to that of electroporation-derived transformants. Our findings therefore lend support to the potential use of transduction of vaginal Lactobacillus species as a novel strategy for the prevention of HIV infection across mucosal membranes.

A leader in the search for a vaccine against HIV, which causes AIDS, said that recent advances have given scientists new reason for hope.

In an interview with The Associated Press, Dr. Alan Bernstein, executive director of the Global HIV Vaccine Enterprise, cited the world's first successful AIDS vaccine. In September, researchers said the vaccine protected one in three people from getting HIV in a large study in Thailand. Bernstein also pointed to recent progress in determining whether people with HIV produce antibodies that could lead to a vaccine guarding against a variety of forms of HIV. He also said there is progress in mapping the many variations of what he called a "clever virus" that has so far eluded vaccine efforts because it kills some of the key cells needed to make a vaccine.

"This is a very exciting time in the field," Bernstein said. "A vaccine is possible, and we have the scientific tools now to turn that possibility into a reality." Though he said the research effort has turned a corner after several setbacks, he cautioned a vaccine was still several years away.

Salim Karim, director of the Centre for the AIDS Programme of Research in South Africa, said he was not optimistic. "I wish I could say I was. But I'm not. It's proving to be a challenge that's more complex than previously thought," Karim said, adding he has spent 15 years researching a vaccine, and expected success to take at least another 15. Karim called the Thai study a "glimmer." Scientists must now try to improve the vaccine so that it protects more than a third of the people who get it, and lasts for more than the six to 12 months it now appears to be effective.

Questions have been raised about whether an HIV vaccine was possible, and even whether it made sense to devote time and energy to the pursuit. Bernstein said a comprehensive approach, that includes finding a vaccine, must be taken against AIDS.

     Background: The V3 loop of the HIV-1 envelope (Env) glycoprotein gp120 was identified as the "principal neutralizing domain" of HIV-1, but has been considered too variable to serve as a neutralizing antibody (Ab) target. Structural and immunochemical data suggest, however, that V3 contains conserved elements which explain its role in binding to virus co-receptors despite its sequence variability. Despite this evidence of V3 conservation, the ability of anti-V3 Abs to neutralize a significant proportion of HIV-1 isolates from different subtypes (clades) has remained controversial.
     Methods: HIV-1 neutralization experiments were conducted in two independent laboratories to test human anti-V3 monoclonal Abs (mAbs) against pseudoviruses (psVs) expressing Envs of diverse HIV-1 subtypes from subjects with acute and chronic infections. Neutralization was defined by 50% inhibitory concentrations (IC50), and was statistically assessed based on the area under the neutralization titration curves (AUC).
     Results: Using AUC analyses, statistically significant neutralization was observed by >=1 anti-V3 mAbs against 56/98 (57%) psVs expressing Envs of diverse subtypes, including subtypes A, AG, B, C and D. Even when the 10 Tier 1 psVs tested were excluded from the analysis, significant neutralization was detected by >=1 anti-V3 mAbs against 46/88 (52%) psVs from diverse HIV-1 subtypes. Furthermore, 9/24 (37.5%) Tier 2 viruses from the clade B and C standard reference panels were neutralized by >=1 anti-V3 mAbs. Each anti-V3 mAb tested was able to neutralize 28-42% of the psVs tested. By IC50 criteria, 40/98 (41%) psVs were neutralized by >=1 anti-V3 mAbs.
     Conclusions: Using standard and new statistical methods of data analysis, 6/7 anti-V3 human mAbs displayed cross-clade neutralizing activity and revealed that a significant proportion of viruses can be neutralized by anti-V3 Abs. The new statistical method for analysis of neutralization data provides many advantages to previously used analyses.

About 2 000 doctors, nurses and pharmacists have come out of retirement to provide voluntary help in a massive national drive to HIV-test 15-million South Africans. Medical schools have also agreed to release final-year students to assist with testing, while the NGO sector has mobilised 9 000 lay counsellors as part of the programme. In an interview this week Health Minister Aaron Motsoaledi said that South Africa has little choice but to push ahead with the National HIV Counselling and Testing (HCT) campaign -- despite the country's crumbling health system.

"The country is going through a very serious pandemic, the biggest in the world, and we have to deal with it," Motsoaledi said this week. He said the health department has been preparing for the campaign, which kicks off this Sunday, since last year. "For the moment we have got enough condoms and testing kits to start. To sustain it we're staggering the programme over 15 months and over two budgetary years," he said.

During the campaign, which is coordinated by the South African National Aids Council (Sanac), the health department seeks to test 15-million people -- one-third of the population -- by June next year. The rollout will begin in nine high-priority districts, one in each province, before moving to the others. Under the theme of "taking responsibility for oneself", the drive will encourage people to adopt a healthier lifestyle. In addition to testing for HIV medics at the country's testing stations will offer to test for hypertension, diabetes, anaemia and TB.

Motsoaledi said this was a deliberate attempt to bring the country back to a preventative healthcare approach. "In the past 10 years South Africa has gravitated towards a curative healthcare system, which is much more expensive," he said. Salim Abdool Karim, director of the Centre for the Aids Programme of Research in South Africa, said the HCT campaign is "absolutely" the right approach for the country. "Of all the things that we could be doing, in my opinion, this programme is probably the most appropriate at this point," he said.

Also see related articles:
South Africa launches massive UN-backed HIV prevention drive
South Africans praise latest HIV/AIDS testing campaign
South Africa redoubles efforts against AIDS

     Objective: Daily HIV anti-retroviral pre-exposure prophylaxis (PrEP) is being evaluated in clinical trials among men who have sex with men (MSM). However, daily PrEP may not be congruent with sexual exposure profiles of MSM. Here we investigate sex frequency and sex planning to identify and inform appropriate PrEP strategies for MSM.
     Methods: We evaluated sex frequency and sex planning in a cohort HIV-negative MSM in Bangkok, Thailand. chi2 test was used to compare reports of sex on different weekdays; logistic regression was used to identify predictors of sex frequency and sex planning.
     Results: Of 823 MSM (mean age 28.3 yrs) 86% reported sex on 2 days per week or less and 65% reported their last sex to have been planned. Sex on the weekend (~30%) was more often reported than sex on weekdays (~23%). In multivariate analysis, use of alcohol, erectile dysfunction drugs, group sex, sex with a foreigner, buying and selling sex and a history of HIV testing were associated with having sex on 3 days per week or more; age 22 to 29 years, not identifying as homosexual, receptive anal intercourse and not engaging in group sex were associated with unplanned sex.
     Conclusion: Intermittently dosed PrEP (as opposed to daily) may be a feasible HIV prevention strategy and should be considered for evaluation in clinical trials. Predictors of sex frequency and sex planning may help to identify those in need for daily PrEP and those who may not be able to take a timely pre-exposure dose.

     Objective: Systematically assess the effectiveness of HIV-prevention interventions in changing sexual behaviour of young people (10-25 years) in sub-Saharan Africa.
     Methods: Three online databases were searched using prespecified terms. Additional articles were identified on websites of international organizations and by searching bibliographies. Randomized and nonrandomized trials of interventions aiming to reduce risk behaviour were included as well as single-arm studies reporting effects of differential exposure to an intervention. Data were extracted independently in duplicate using predefined data fields.
     Results: Thirty-one studies on 28 interventions met the inclusion criteria, including 11 randomized trials. Difficulties with implementing planned activities were reportedly common and differential exposure to intervention was high. Two hundred and seventeen outcome measures were extracted: 88 early (within 1 year of intervention) and 129 late outcomes (more than 1 year after the end of the intervention). Sex education and condom promotion among youth did not increase sexual behaviour as well as risky sexual behaviour. No positive effects on sexual behaviour were detected either and condom use at last sex only increased among males [relative risk = 1.46; 95% confidence interval = 1.31-1.64]. One study reported a reduction of herpes simplex virus-2, but not HIV incidence.
     Conclusion: There remains a stark mismatch between the HIV burden in youth and the number of attempts to design and test prevention interventions - only two trials report biological outcomes. More effective interventions targeting youth are needed. Attention should go to studying implementation difficulties, sex differences in responses to interventions, determinants of exposure to interventions and perhaps inclusion of other factors apart from HIV/AIDS which influence sexual behaviour.

Michel Sidibe told Reuters countries such as Russia, Ukraine and others could halt or buck the global downward trend in new HIV infections if they ignored the threat posed by drug users and failed to introduce effective "harm reduction" steps. "HIV infection has slowed down globally, but it is expanding in this region of eastern Europe and central Asia," he said. "We're not seeing anything like this in any other region of the world."

Sidibe, who was due to address a conference on harm reduction in the British city of Liverpool on Sunday, said of the 3.7 million people in the region who inject drugs, a quarter have the human immunodeficiency virus that causes AIDS. Drug users, often criminalized and marginalized from health and social services, can spread the virus by sharing needles with an HIV-infected person or pass it on by having unprotected sex. Infection prevention steps like providing needles, condoms and substitute drugs like methadone -- collectively known as harm reduction -- are seen by many experts as key to halting the spread of HIV and AIDS, but some governments are reluctant to provide them for fear of being seen to condone drug use.

Sidibe warned newly-emerging and growing pockets of HIV spread among drug users could propel a wave of infections and undermine gains in curbing sexual transmission of the disease. "What is unacceptable is knowing there is this multitude of epidemics among drug users, we have on average each drug user getting less than two clean needles a month, and only about four percent of those living with HIV getting treatment," he said.

Nontyphoidal Salmonellae are a major cause of life-threatening bacteremia among HIV-infected individuals. Although cell-mediated immunity controls intracellular infection, antibodies protect against Salmonella bacteremia. We report that high-titer antibodies specific for Salmonella lipopolysaccharide (LPS) are associated with a lack of Salmonella-killing in HIV-infected African adults. Killing was restored by genetically shortening LPS from the target Salmonella or removing LPS-specific antibodies from serum. Complement-mediated killing of Salmonella by healthy serum is shown to be induced specifically by antibodies against outer membrane proteins. This killing is lost when excess antibody against Salmonella LPS is added. Thus, our study indicates that impaired immunity against nontyphoidal Salmonella bacteremia in HIV infection results from excess inhibitory antibodies against Salmonella LPS, whereas serum killing of Salmonella is induced by antibodies against outer membrane proteins.

To read an article by Reuters, click here.
To read Moir's and Fauci's perspectives on this study, click here.

Research into a deadly link between salmonella and HIV shows that the AIDS virus damages the immune system in ways doctors did not previously understand, providing new clues for vaccine development.

Salmonella often causes fatal bloodstream infections in people with HIV, particularly in Africa. But although the risk has been known for more than 25 years, it is only now that researchers have a scientific explanation. It is not immune system deficiency that causes the problem but an excess of antibodies. The discovery should help avoid blind alleys in producing new vaccines.

"It's quite a surprise and it suggests that what we are dealing with here is more of a consequence of an immune disregulation as opposed to an immune deficiency per se," said lead researcher Cal MacLennan of the University of Birmingham.

Human immunodeficiency virus (HIV) is normally thought of as a virus that stops the immune system working because it kills so-called CD4 cells that orchestrate the body's response to foreign invaders. In the case of salmonella, however, MacLennan and colleagues found that blood from HIV-infected adults contained high levels of antibodies to salmonella. The snag was the antibodies stuck to the wrong part of the bacteria and so failed to kill them.

The research, published in the journal Science on Thursday, indicates that the body's immune response is very different in patients infected with HIV compared to those without HIV -- and it is not simply a question of less immune response. The discovery is important both for doctors trying to work out how to treat people with HIV and for developers of vaccines intended to protect HIV-positive patients against other infectious diseases. It may also help in the hunt for an effective vaccine against salmonella, if only by showing some present approaches are misguided.

For more information: MacLennan CA, Gilchrist JJ, Gordon MA, et al. Dysregulated Humoral Immunity to Nontyphoidal Salmonella in HIV-Infected African Adults. (23 April 2010) Science 328 (5977), 508.

     Background The ability of researchers to provide sustainable care to individuals who acquire HIV during participation in HIV prevention trials has rapidly expanded along with national treatment options. The Methods for Improving Reproductive Health in Africa (MIRA) trial (2003-2006), a phase III multi-site randomized controlled trial, measured the effectiveness of the diaphragm used with Replens(R) lubricant gel in preventing heterosexual acquisition of HIV among women in Zimbabwe and South Africa. The MIRA Standard of Care program, which started towards the end of the trial period and continued for 5 months after trial closeout, enabled women who acquired HIV during the trial to receive additional counseling and clinical care and facilitated links to long-term HIV-related care and treatment from public health facilities.
     Purpose To describe eligible participants’ uptake of these optional services and evaluate the program’s strengths and limitations.
     Methods All women who acquired HIV during their MIRA participation were re-contacted and invited to return to the study clinics for additional care and referrals. Sites reported monthly statistics of uptake of services.
     Results From start to end, 185 of 323 (57%) HIV-positive participants accepted additional care; 81 (25%) could not be relocated. 142 (44%) women received referrals to government healthcare facilities and 90 (28%) enrolled in wellness/treatment programs. Fifty-seven (18%) declined further care, but reasons for doing so were not recorded systematically.
     Limitations The program began after most participants had exited from the MIRA trial and required re-contacting women, resulting in difficulty in locating some participants.
     Conclusions In the future, care for participants who seroconvert should be offered at the trial onset and fully integrated into clinical trials to avoid losing these participants for further care. More research is needed to identify and understand perceived barriers to establishing a continuum of care between clinical trials and public sector health facilities.

A global pullback on commitments to fund and fight AIDS is resulting in restrictions on the number of people being enrolled into treatment programmes, more frequent drug shortages, and reduced national AIDS budgets, says a new report. An estimated four million people in the developing world have begun HIV treatment, thanks largely to programmes such as the US President's Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis and Malaria, says the report from the International Treatment Preparedness Coalition, which campaigns to improve access to treatment. But resources are insufficient to provide treatment to another six million people who should be getting it. The second figure would rise by an additional three to five million people if all HIV and AIDS programmes were to adopt the December 2009 HIV treatment guidelines of the World Health Organization.

In 1993, the Food and Drug Administration gave its stamp of approval to a then-novel item: the female condom. At the time, AIDS awareness was growing. NBA star Magic Johnson had announced he was HIV-positive less than two years earlier. But the virus was still greatly feared and misunderstood. Condom use was urged as a matter of dire public health, and so women finally could protect themselves if their partner chose not to. Yet according to the Center for Health and Gender Equity, in 2007 about 11 billion male condoms were circulated worldwide compared with 26 million female ones. Cost used to be an issue, but it is no longer: The $4 female condom has been replaced by the 82-cent one.

Though women have, indeed, come a long way, when it comes to sexual equality, we apparently still have a long way to go. But perhaps change is on the way. I live in Washington, D.C., and if I walk into a participating beauty salon, convenience store or high school, the FC2 female condom (FDA-approved last year) is available free of charge. Washington's campaign to protect women is being promoted through a $500,000 grant from the non-profit MAC AIDS Fund.

Washington has been ravaged by HIV/AIDS, with the highest rate in the country: Over 3% of adults are infected, according to a 2009 epidemiology report. Over a quarter of those are believed to be women. Chicago has launched a female condom awareness campaign, too, and hopefully, other cities will follow.

Women are more vulnerable to contracting sexually transmitted diseases than men, medical research shows. Still, most public funding and marketing efforts have focused only on the male condom.

The search for an effective HIV vaccine now moves to Kenyan babies, who will for the first time volunteer in studies that will kick off later in the year. Screening of the parents whose babies will participate in the trials is underway at the Kenya Aids Vaccine Initiative (Kavi) offices located within Kenyatta National Hospital. Previously, HIV vaccine trials have been conducted in adults, with babies and adolescents exempted. But this time around 76 babies aged about five months will be the subjects.

"The involvement of the infants is to help us understand the best time this vaccine should be given to offer a better immunological response," says Prof Walter Jaoko, Kavi deputy director and the vaccine's principal investigator. Many of the current childhood disease vaccines are given to infants to help them develop a stronger immunity against illnesses at a very early age. This forms the basis for testing the HIV vaccine in infants.

Male partners
According to Prof Jaoko, those being enrolled are pregnant women. So far, 12 such women have been screened to determine if they and their yet-to-be born babies qualify to participate in the study. Unlike in other HIV researches, Kavi scientists are also seeking the consent of the women's male partners before enrolling the infants in the trial. Both the man and the woman are taken through what the research entails, before appending their signatures on the consent form.

An HIV vaccine is possible if the world works together as a global community with the objective of finding one, but it will take some years to develop. This is according to Dr Alan Bernstein of the Global HIV Vaccine Enterprise.

The 2009 results of an HIV vaccine trial in Thailand showed for the first time that a vaccine could cut the risk of HIV infection. The trial vaccine was a combination of two experimental vaccines that on their own had not been able to cut the risk of infection. However, combined, the risk of infection was cut by a third. Bernstein was in South Africa for talks with the WHO and UNAIDS to discuss the breakthrough of the experimental HIV vaccine. He believes a collaborative effort from academia, industry, public and private funders will speed up the search for a vaccine.

Excerpts of the interview follow.
Q: In 2009 the Thailand vaccine trial cut the risk of HIV infection for the first time. What is most significant about these trial results?
A: The most important thing is that it has opened a door which we did not have before. It says that it is possible to get protection against HIV acquisition with a vaccine.

Q: What significance does the result of the Thai vaccine trial hold for the African strain of the HIV Virus?
A: We came to a consensus that we have to do two things. We have to do more in Thailand, and, in sub-Saharan Africa, where the epidemic is. There needs to be a trial that tests other variations of what was done in Thailand.

There's no such thing as the Car or the Shoe or the Laundry Soap. But everyone knows the Pill, whose FDA approval 50 years ago rearranged the furniture of human relations in ways that we've argued about ever since.

Consider the contradictions: It was the first medicine ever designed to be taken regularly by people who were not sick. Its main inventor was a conservative Catholic who was looking for a treatment for infertility and instead found a guarantee of it. It was blamed for unleashing the sexual revolution among suddenly swinging singles, despite the fact that throughout the 1960s, women usually had to be married to get it. Its supporters hoped it would strengthen marriage by easing the strain of unwanted children; its critics still charge that the Pill gave rise to promiscuity, adultery and the breakdown of the family. In 1999 the Economist named it the most important scientific advance of the 20th century, but Gloria Steinem, one of the era's most influential feminists, calls its impact "overrated." One of the world's largest studies of the Pill -- 46,000 women followed for nearly 40 years -- was released this March. It found that women who take the Pill are less likely to die prematurely from any cause, including cancer and heart disease, yet many women still question whether the health risks outweigh the benefits.

Maybe it's the nature of icons to be both worshipped and stoned, laden with symbolic value beyond their proportions. Because the Pill arrived at a moment of epochal social change, it became a handy explanation for the inexplicable.

     Background: The performance of coital diaries (CDs) and clinic-based interviews to measure sexual behavior was compared during a pilot study for a Phase III microbicide trial.
     Methods: In Mwanza, 59 women were enrolled for 4 weeks and provided with 20 placebo gels. Weekly, women were given CDs to complete daily. At the final clinic visit, women attended a face-to-face interview (Clinic FFI) about their sexual behavior, and the gel use was accounted for (gel accountability (GA)). Comparisons were made between CD, Clinic FFI, and GA data. In-depth interviews following clinic visits elicited reasons for discrepancies in reports.
     Results: Twice as many sex acts during 1 week were recorded in the CD (median 4) compared with the clinic FFI (median 2). At the clinic FFI, more women reported using the gel for each sex act (84% vs. 40%; P < 0.001) and vaginal washing for each sex act (98% vs. 56%; P < 0.001) compared with the CD. Over 4 weeks, 16.4% of women recorded sex during menstruation in CDs compared with 1.8% at the clinic visit (P = 0.01). The median number of gels used reported in the CDs was the same as the GA (10) with 59% agreement on the number used within +/-2 gels. Reasons for misreporting during clinic FFI were reported to have been poor recall, embarrassment, or misunderstanding. Inaccuracies in CDs were attributed to misunderstanding or poor recording.
     Conclusions: CDs elicited higher recording of sex acts and lower reporting of gel use than clinic FFIs, which has implications for measuring adherence during clinical trials. With clear instructions and support, coital dairies should be considered in future microbicide trial design.

Days before travelers worldwide are to begin arriving for Shanghai's world exposition, China has lifted a two-decade ban on travel to the country by people who carry the virus that causes AIDS or who have other sexually transmitted diseases. The action also removed a longstanding ban on travel to China by people with leprosy.

The government approved amendments to a 1986 law governing quarantines and a 1989 law regulating entry by foreigners, removing prohibitions related to people with H.I.V., which causes AIDS, China's State Council, a body roughly equivalent to the White House cabinet, reported on its Web site late Tuesday. The council's standing committee approved the changes on April 19 and Premier Wen Jiabao signed decrees putting them into effect on April 24, the council said.

With the changes, the ban on travel is officially limited only to people with infectious tuberculosis, serious mental disorders and "infectious diseases which could possibly greatly harm the public health."

China has temporarily lifted the ban on H.I.V.-positive travelers for major events in the past, but the revision of longstanding laws indicates that the latest change will be permanent. The state-run newspaper China Daily quoted a spokesman for the health ministry, Mao Qun'an, as saying that the ministry had been working to permanently remove the prohibition since the 2008 Beijing Olympics.

One year ago, Obama unveiled a new $63 billion global health initiative. So why are advocacy groups raising the alarm about HIV treatment shortages?

Peter Mugyenyi runs the Joint Clinical Research Center (JCRC), one of the most successful AIDS-treatment providers in Uganda. Back in 2003, he went to Washington on a day's notice to help the Bush administration draft its plan for what would become PEPFAR (the President's Emergency Plan for AIDS Relief), the most ambitious public-health initiative ever to tackle the AIDS crisis, then sat beside Laura Bush at the State of the Union address when the program was announced. In the years since, he has been applauded when he exceeded his enrollment targets.

But today, despite treating 32,000 AIDS patients, he does not have a message of success. Instead, he was back in Washington in March, this time to warn that the stagnation of PEPFAR funding is beginning to "result in chaos." At the beginning of April he was quoted in The Boston Globe, announcing that he had received word not to enroll new patients unless they are replacing others who have left or died. Midmonth, Health GAP, an independent activist organization, reported that antiretroviral-treatment programs at the JCRC and other clinics in Uganda were being "precipitously" transferred to government hospitals, which did not have the drugs to handle them. On Monday, Mugyenyi was again raising the alarm, having penned the introduction to a new report put out by the International Treatment Preparedness Coalition that warns of a global backslide in the AIDS fight.

Over the past year, the Obama administration has rolled out plans for a new, more pragmatic approach to U.S. global-health initiatives. As NEWSWEEK wrote in the fall, the plan was to get more results for less money, something health experts believed they could achieve by diversifying the U.S. global-health portfolio beyond the singular orientation of PEPFAR and teaming up with multilateral partnerships, like the Geneva-based Global Fund. This would allow HIV clinics to treat an array of health issues, including those not related to HIV, and stabilize funding for a variety of health concerns, independent of transitory fundraising pushes for the cause du jour...

AIDS advocates are now wondering whether "pragmatic" is just a euphemism for cheap. In the last year, the number of HIV-positive people that PEPFAR started on treatment was the smallest it has been for four years, even while demand increases as patients live longer and the disease continues to spread unabated.

To view additional coverage of this topic in Reuters, click here.
To read the full report from the International Treatment Preparedness, Rationing Funds, Risking Lives: World Backtracks on HIV Treatment, click here.

Millions of heroin users around the world are at unnecessary risk of HIV and other infections because donors are underfunding projects to reduce harm in these groups. That is the conclusion of a report published this week by the International Harm Reduction Association. Harm reduction projects supply clean syringes, heroin substitutes, and outreach. On the basis of an epidemiological assessment the report recommends that philanthropic organisations spend a fifth of HIV prevention budgets on harm reduction among drug users.

"The amount being spent is pretty appalling. About 15-20 times more is needed to have any effect," said Gerry Stimson, lead author of the report and director of the association, a non-governmental organisation that focuses on public health and human rights and that works closely with the United Nations. "So few organisations fund this," he said. "The Gates Foundation hardly funds harm reduction at all.

A new generation of clinical trials could yield breakthroughs, but must be handled with care.

At the American Association for Cancer Research annual meeting in Washington DC last week, a recurrent theme was complexity. The deeper scientists have delved into the fundamental nature of cancer, the more they have come to recognize its vast genetic diversity, which can make even tumours of the same cancer type seem unrelated.

It is encouraging to see researchers embracing new methods to deal with that complexity. One especially promising technique highlighted in several talks was the 'adaptive' clinical trial, which allows researchers to avoid being locked into a single, static protocol for the duration of the trial. Instead, investigators can evaluate data as they come in, and use that information to change a trial's structure.

Such flexibility is particularly important in cancer research. Investigators have struggled to plan clinical trials that can incorporate an ever-proliferating list of molecular biomarkers -- features such as mutations or gene-expression patterns that can be used to distinguish one person's tumour from the next person's. The idea is to find markers that can identify a subset of people for which a given therapy is working, even when it seems to have little effect on the patient population as a whole. Adaptive trials thus allow investigators to analyse the data midstream, correlate those results with known biomarkers, and then alter the course of the trial in light of that information -- perhaps by enrolling additional people with cancer on the basis of their biomarker status. The trial then continues, targeting those people most likely to benefit.

Researchers have dabbled with such experiments for years. But it was only in 2007 that the European Medicines Agency (EMA) published a paper outlining appropriate adaptive-trial conduct, and only in February 2010 that the US Food and Drug Administration (FDA) followed suit with its draft guidance to industry. The FDA draft is open for public comment until 1 June.

"Undertaking adaptive clinical trials is an experiment in itself: there is much still to be learned about the unforeseen pitfalls, and what the best practices are."

     Objective: HIV+ elite controllers are a unique group of rare individuals who maintain undetectable viral loads in the absence of antiretroviral therapy. We studied immune responses in these individuals to inform vaccine development, with the goal of identifying the immune correlates of protection from HIV.
     Methods: We compared markers of cellular activation, HIV-specific immune responses and regulatory T (Treg) cell frequencies in four groups of individuals: HIV-negative healthy controls, elite controllers (HIV RNA level <75 copies/ml), individuals on HAART and individuals with HIV RNA level more than 10 000 copies/ml (noncontrollers).
     Results: Elite controllers possessed significantly lower levels of activated HIV-specific CD8+ T cells and of recently divided HIV-specific CD4+ T cells than noncontrollers, whereas these differences were not seen in the respective cytomegalovirus-specific T-cell populations. Elite controllers also mounted a stronger and broader cytokine and chemokine response following HIV-specific stimulation than individuals on HAART and noncontrollers. Finally, we found that HAART-suppressed individuals had elevated Treg cell frequencies, whereas elite controllers and noncontrollers maintained normal percentages of Treg cells.
     Conclusion: Elite controllers maintain high levels of HIV-specific immune responses with low levels of HIV-specific T-cell activation and do not have elevated Treg cell levels. Based on these data an ideal HIV vaccine would induce strong HIV-specific immune responses whereas minimizing HIV-specific T-cell activation.

Uganda's community of prostitutes has long been considered a weak link in the fight against Aids. Popular opinion holds that most of them are infected with HIV--that they remain powerless to play the kind of positive role that contributes to the bigger picture. But that may be about to change. Now, with the efforts of progressive lawyers, doctors and some charismatic sex workers, suddenly prostitutes are being told that they are powerfu--that they can fight the pandemic like never before. Inside the gated compound of an ordinary house off Salaama Road, in Makindye, some 55 sex workers yesterday met under a white tarpaulin to hear this hopeful message.

They were not being told to quit the oldest profession; they were being asked to embrace it with responsibility, guile and resourcefulness. If they could do it, for example by insisting on their clients wearing condoms, they could accomplish a lot more than many unfaithful couples. The message seemed to resonate well among the sex workers, including two men among them.

The speaker, Dr Ben Twinomugisha, a Makerere University law professor, said he rejected the assumption that all sex workers were infected with HIV. His speech sounded like a sermon in courage, telling the women to reject the sympathy of those who look down upon them.

Vaginal microbicides currently under development are substances that may prevent the transmission of HIV. Qualitative, in-depth post-trial interview data from a Phase III clinical trial of 6% Cellulose Sulfate microbicide gel in two sites in Africa (Uganda and Benin) and two in India (Chennai and Bagalkot) were examined in order to better understand factors that influence microbicide acceptability and adherence in a clinical trial setting. Women found the gel relatively easy to use with partners with whom there were no expectations of fidelity, in situations where they had access to private space and at times when they were expecting to engage in sexual intercourse. Adherence to gel seemed significantly more difficult with primary partners due to decreased perceptions of risk, inconvenience or fear of partner disapproval. Findings suggest that women in a variety of settings may find a microbicide gel to be highly acceptable for its lubricant qualities and protective benefits but that adherence and consistent use may depend greatly on contextual and partner-related factors. These findings have important implications for future trial designs, predicting determinants of microbicide use and acceptability and marketing and educational efforts should a safe and efficacious microbicide be found.

The International AIDS Vaccine Initiative (IAVI) and Lentigen today announced a collaboration to design a preventive AIDS vaccine based on Lentigen's technology. The candidate AIDS vaccine will be devised to safely mimic biological aspects of HIV infection and tested first in pre-clinical studies as part of an initial 18-month agreement. Lentigen's technology relies on a synthetic version of a virus related to HIV that has been engineered, along with other safety modifications, to be incapable of inserting itself into the human genome.

Some of the most effective vaccines used in humans are live but attenuated versions of disease-causing viruses--viruses that, in other words, have been rendered incapable of causing disease. But this approach is considered too risky for HIV vaccine development. Scientists fear that attenuated HIV might mutate and become pathogenic again, or insert itself into the genome and do so later. The use of Lentigen's technology could, however, allow researchers to come remarkably close to the live-attenuated strategy without raising such concerns.

"We believe that this prototype vaccine has the potential to generate the protective immune responses seen with experimental live-attenuated viruses, but without their pathogenic effects," said Dr. Boro Dropulic, Chief Scientific Officer and a founder of Lentigen.

The collaboration is a part of IAVI's Innovation Fund, a program launched to support the application of novel and unconventional technologies to AIDS vaccine design and development, and supported by the Bill & Melinda Gates Foundation.

Immunovaccine and the Dana-Farber Cancer Institute are to collaborate on formulating the latter's HIV protein antigens on Immunovaccine's DepoVax(TM) vaccine-enhancement and delivery platform. The goal is to evaluate whether the DepoVax technology will boost the resulting vaccine's ability to generate immune responses.

Immunovaccine's patented DepoVax platform is an evolution of the firm's original finding that formulating immunogens in liposomes and then in an oil carrier results in significantly enhanced immune responses. The final DepoVax technology is actually a dry product that is inherently stable, the company claims. Once reconstituted for injection, the active components are retained in the oil phase. Immunovaccine says that this allows a long-lasting depot effect that elicits potent humoral and/or cellular immunity after just one dose.

The company's lead therapeutic candidate is the anticancer vaccine DPX-0907. The Phase I trial started enrolling patients last month. The study will enroll up to 24 patients with advanced breast, ovarian, or prostate cancer. DPX-0907 combines seven essential peptide antigens with the DepoVax delivery platform.

The Bill and Melinda Gates Foundation announced today that Ernest Loevinsohn will join the Global Health Program as Director of Policy and Advocacy on June 21. Loevinsohn has more than twenty years of experience applying strategic vision to complex international issues, most recently with the Canadian International Development Agency (CIDA).

Loevinsohn will lead the foundation's efforts to encourage political commitment and effective investment in global health in both donor and developing countries. He will also manage a grant program, oversee work to build evidence to support effective policy making, and help lead the foundation's work on the Global Fund to Fight AIDS, Tuberculosis, and Malaria.

"Ernest's deep personal commitment to global health is matched by his strong track record working with governments, aid experts, and advocates around the world," said Dr. Tachi Yamada, president of the Global Health Program. "His wealth of experience will help ensure that our advocacy work has impact and saves lives."

The Global Health Policy and Advocacy team works to inspire sustained public and private commitments that lead to improved health in poor countries. It encourages the policies needed to build a more conducive environment for global health investments and to expedite the creation and delivery of new vaccines, drugs, and other health tools. The team also helps create innovative financing strategies that increase the stability and predictability of funding for global health.

Request For Applications (RFA) Number: RFA-AI-10-008

Key Dates
Release Date: April 23, 2010
Letters of Intent Receipt Date(s): September 22, 2010
Application Receipt Dates(s): October 22, 2010 
Earliest Anticipated Start Date: July, 2011

Executive Summary
     Purpose. The National Institute of Allergy and Infectious Diseases (NIAID) invites applications from institutions/organizations to participate in a cooperative study group focused on immune defense mechanisms and immune regulation at mucosal surfaces including respiratory, gastrointestinal and urogenital tract mucosa. The goal is to break new ground in the understanding of basic mucosal immune defense mechanisms by introducing new ideas, approaches and technologies that address the difficult questions remaining in mucosal immune defense. The knowledge gained would facilitate future development of vaccines and immunotherapies to protect mucosal surfaces from infection and related immunopathologies. The cooperative study group will be composed of a set of cooperative agreement grants governed by a Steering Committee, and will draw upon an Infrastructure and Opportunities Fund to support a range of innovative, collaborative, and pilot/feasibility projects. NIAID encourages submissions from established and new investigators; applicants without a prior track record of funding in mucosal immunity are welcome to apply.
     Mechanism of Support. This FOA will utilize the cooperative agreement (U01) award mechanism.
     Funds Available and Anticipated Number of Awards. For this funding opportunity, budgets up to $250,000 direct costs per year and time periods up to five years may be requested. NIAID expects to allocate approximately $4 million in total costs in FY 2011 to fund seven to nine awards.
     Budget and Project Period. The total project period for an application submitted in response to this funding opportunity may not exceed 5 years. Direct costs are expected to range between $200K and $250K per year.

While most safer sex and HIV prevention programmes are negative and disease-focused, The Pleasure Project is different: they take a positive, liberating and sexy approach to safer sex. Think of it as sex education ... with the emphasis on 'sex'. Join IRMA and The Pleasure Project's Anne Philpott for a global teleconference to take sexy back in our prevention work. Visit the Pleasure Project here.

Tuesday, May 11, 2010
8:30 PM - India
8:00 AM - Los Angeles
10:00 AM - Chicago, Lima
11:00 AM - Ottawa, New York, DC
4:00 PM – London, Lagos
5:00 PM - Cape Town, Barcelona

If you would like to participate, please send an email to rectalmicro@gmail.com.