January
Merck HIV Vaccine Efficacy Trial Launched
A 1,500-person phase IIB efficacy trial of an HIV vaccine candidate developed by Merck officially gets underway. The trial will attempt to ascertain whether the vaccine can prevent HIV infection and/or prevent or delay disease progression in vaccine recipients that become infected. The study is in collaboration with the NIH-sponsored HIV Vaccine Trials Network (HVTN). TAG wrote extensively about the planning of this trial in 2004, see "One Step Forward: Merck Vaccine Moves Forward with Efficacy Trial" http://www.aidsinfonyc.org/tag/tagline/0407.html#2

February
Attack of the Supervirus

"We've identified this strain of HIV that is difficult or impossible to treat. Potentially, no one is immune."
Thomas Frieden MD, Commissioner of Health for New York City, Press Conference, February 11, 2005

A media maelstrom ensued when the NYC Department of Health, along with David Ho and Marty Markowitz from the Aaron Diamond AIDS Research Center (ADARC) announced the discovery of what was quickly dubbed a "supervirus." A New York City man had become infected with multi-drug resistant HIV that appeared to have caused rapid disease progression and the infection was thought to have occurred during a period where the man had multiple sex partners and was using crystal meth. The accusatory hand wringing that followed brought back unpleasant memories of the earliest days of the AIDS epidemic, when a public fascination for tales of drugs and debauchery sold papers while demonizing gay men in the process. In this case, as then, the scientific realities of what was being dealt with – a virus – were largely ignored in service of a compelling narrative.

A year later, it's still not entirely clear what happened. The virus population in the individual had properties that have previously been associated with rapid progression, namely the ability to use both the R5 and X4 co-receptors. But it has also been suggested that this may have been a case of dual infection (where two viruses are acquired either simultaneously or in close succession) and, although relatively rare, dual infection is typically associated with rapid progression, as is well documented in the scientific literature. Although ADARC clearly know how to look for dual infection (they published on a case many years ago), they have not been forthcoming about any analyses they have performed in this particular case. There was certainly evidence of resistance to all but two drugs (although again, transmission of drug resistant virus is not a new phenomenon), but the individual has reportedly responded well to therapy, albeit a rather complex and arduous regimen including Fuzeon. Further cases of infections with similar viruses have not been reported, although notorious huckster Dr. Gary Blick claimed to have identified the source of the infection (one of his patients in Connecticut) at the IAS Meeting in Rio in July of 2005. This data has not been published. In its own 2005 Year in Review, the journal Nature Medicine awarded the ADARC scientists involved in this case a D-. The NYC Department of Health, apparently eager to shock people out of complacency regarding the risk of HIV infection, appear to have instead promulgated a scientifically unsupported scare story and dented their own credibility in the process.

It Takes Guts
At the annual Retrovirus conference in a wintry Boston, the pointless cacophony generated by the supervirus story was quieted a little by a well-received presentation on HIV pathogenesis delivered by Danny Douek, a rising star of immunology working at the NIH's Vaccine Research Center. Drawing on macaque studies published by Ron Veazey and Andrew Lackner, Douek outlined the potential importance of the gut as a site of HIV replication and rapid CD4 T cell depletion, from the very earliest timepoints after infection. Douek presented data showing that, as in macaques, HIV appears to quickly eliminate most CCR5-expressing CD4 T cells from the human gut and that this dramatic loss persists even after HAART is initiated. Douek went so far as to suggest that people lose ~50% of their memory CD4 T cells within months of becoming HIV infected, although some skeptics expressed surprise that such a loss can be sustained for an average of 10 years without any clinical consequences. Douek also posited that perhaps this effect of HIV allows bacteria normally localized to the gut to spread elsewhere in the body and contribute to the systemic immune activation that is seen in people with HIV, although he stressed that this was highly speculative. Douek's study was published in the journal Nature in April along with similar work conducted by Ashley Haase's group in Minnesota. However, recent reports have shown that Sooty Mangabey monkeys – who typically experience no ill effects from infection with HIV's simian sibling SIV and have few CCR5-expressing CD4 T cells – also experience a dramatic apparent loss of CD4 T cells from the gut if they are SIV infected. This finding may call into question Douek's contention that the gut is central to HIV pathogenesis.

Tenofovir PreP Trial in Cameroon Suspended
A trial assessing the efficacy of tenofovir in preventing HIV infection (an intervention known as pre-exposure prophylaxis or PreP) among high-risk Cameroonian sex workers is stopped by the Cameroon Health Ministry. The decision followed a drumbeat of community protests that unfortunately cloaked several valid concerns about the conduct of the trial with a veil of overheated rhetoric that has helped foster a widespread distrust of prevention research in general. An ongoing dialogue between community stakeholders, researchers and the trial's funders took place over the course of 2005 in an attempt to address this issue and facilitate future trials of tenofovir PreP.

March
Another Tenofovir PreP Trial Bites the Dust
Another tenofovir PreP trial, this time in Nigeria, is cancelled by the primary sponsor Family Health International (FHI). The cancellation is reportedly the result a failure of local researchers to meet "necessary scientific standards." Bizarre press quotes from Ward Cates, president of FHI's Institute for Family Health, comparing the status of the trials to Goldilocks ("This is like Goldilocks," he said. "In Cameroon, it was too politically hot. In Nigeria, it was too operationally cold. In Ghana, so far, it's just right") incline many to wonder about what kind of standards the trial's sponsors are being required to live up to. Tenofovir PreP trials were originally planned for Nigeria, Cambodia, Ghana, Cameroon and Malawi but, at this point, only Ghana remains an active study site.

July
Merck HIV Vaccine Trial Expands
Some strange but good news about Merck's HIV vaccine trial popped up at a community meeting in July. The vaccine uses an attenuated form of adenovirus serotype 5 (Ad5 for short) as a vector for delivering HIV proteins into the body and triggering HIV-specific CD4 and CD8 T cell responses. But a problem with Ad5 is that it is common in nature (it causes severe colds) and many people have high levels of antibodies against it. These antibodies greatly reduce the ability of the Ad5 vaccine to trigger HIV-specific T cell responses. At least, this was what was believed based on preliminary studies using a version of the vaccine that encoded just a single HIV protein, Gag. But for the phase IIB efficacy trial Merck switched to a construct that encoded Gag, Pol and Nef. Surprisingly, when the impact of antibodies against Ad5 on this new construct was assessed, it turned out that the levels of HIV-specific T cell responses were not reduced as severely. This has led Merck and the HVTN to add another 1,500 volunteers to their trial, without regard to their levels of anti-Ad5 antibodies (the initial study design excluded anyone with an antibody titer over 200).

August
CANVAC Undercut
Grim news for the Canadian Network for Vaccines and Immunotherapeutics: despite an excellent assessment by a panel of expert reviewers, the Canadian government's Network of Centres of Excellence Selection Committee mystifyingly decides not to fund CANVAC's proposal for a second 7-year cycle of funding. Researchers in this Network have conducted critically important research on many topics, including the correlates of immune protection against HIV infection in exposed seronegative individuals. While it is hoped that CANVAC can continue and supplement their funding from other sources, the decision is yet another blow to the already benighted fields of vaccines and immune-based therapies.

September
Concerns Arise Over Co-Receptor Blockers
After a period of considerable optimism regarding a new class of antiretrovirals that target the CCR5 co-receptor (used by HIV to gain entry into CD4 T cells), one such candidate - GSK's aplaviroc - is suddenly discontinued due to several cases of potentially severe liver toxicity in study participants. Schering Plough's vicriviroc falls by the wayside shortly afterwards as a result of underwhelming anti-HIV activity. Only Pfizer's maraviroc survives, and its future is also clouded by scare regarding a single case of severe liver toxicity in a trial participant; the incident is currently thought to have been unrelated to maraviroc but concerns linger regarding this entire class of drugs.

October
Vaccine Protection Against Human Papilloma Virus
Undoubtedly the biggest news of 2005 in terms of the potential impact on global human health was Merck's October announcement that their HPV vaccine candidate - dubbed GARDASIL - showed 100% protection against high-grade cervical pre-cancers and non-invasive cervical cancers associated with HPV types 16 and 18 (thought to be responsible for around 70% of HPV-related cervical cancers) in an ongoing efficacy trial in women. In December, Merck filed for approval with the FDA, a hearing is anticipated in early 2006. It is believed that data from an ongoing trial in gay men (in whom HPV infection can cause anal cancer) will also be part of the submission.

November
Novel Microbicides Show Promise
The microbicide field got a fillip from a study published in the November 3rd issue of the journal Nature. A research group led by John Moore at Cornell University in New York evaluated combinations of HIV inhibitors that target different stages of the virus-cell attachment and entry process as potential microbicides in a macaque model. Several combinations proved highly efficacious at preventing SHIV infection, laying the groundwork for moving such novel microbicide combinations into human studies.

2006
News updates from TAG's Michael Palm Basic Science, Prevention, and Vaccines Project are published on an ongoing basis on the Project weblog at: http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/