Back-to-Basics Push as HIV Prevention Struggles
Jon CohenScience 15 February 2008:
BOSTON--At the big annual AIDS conference held in the United States, new drug studies once dominated the agenda. But last week at the 15th Conference on Retroviruses and Opportunistic Infections (CROI), treatment took a back seat to prevention. Many powerful anti-HIV drugs now exist, but few attempts to obstruct HIV infection have succeeded. Results presented at CROI, which ran from 3 to 6 February, continued the string of bad news and prompted much soul-searching about how to invigorate the ailing vaccine search. A few sessions did, however, relieve some of the gloom with reports on new ways to stop HIV's spread from mother to child and new insights into how HIV causes an infection and destroys the immune system.
Vaccine researcher Ronald Desrosiers, head of the New England Primate Research Center in Southborough, Massachusetts, sparked debate by criticizing the funding priorities at the U.S. National Institutes of Health (NIH) in Bethesda, Maryland. NIH devotes nearly one-third of the roughly $600 million it spends annually on AIDS vaccine research to developing and testing products in humans, yet, Desrosiers asserted, no product now under development has "any reasonable hope of being effective." "Has NIH lost its way in the vaccine arena?" asked Desrosiers, who argued for more basic research. "I think it has." (ScienceNOW, 5 February: sciencenow.sciencemag.org/cgi/content/full/2008/205/1.)
The beleaguered AIDS vaccine field took a serious hit last September, when researchers halted a clinical trial of a promising AIDS vaccine after an interim analysis revealed that it offered no protection against HIV. More disconcerting still, some evidence suggests that preexisting antibodies against an adenovirus strain, Ad5, used in the Merck and Co. vaccine to carry HIV genes, may somehow have made people more susceptible to the AIDS virus (Science, 16 November 2007, p. 1048). Data from Susan Buchbinder, an epidemiologist at the San Francisco Department of Public Health in California and co-chair of the study, offered some reassurance that the vaccine did not cause harm. Circumcision protects men from HIV, and uncircumcised men with high levels of Ad5 antibodies appear to have become infected more readily. "The effect of circumcision seemed at least as strong if not stronger than Ad5 [antibodies]," said Buchbinder. Although it's difficult to unravel cause and effect in post-hoc analyses, Buchbinder said: "I don't think at the end of the day that Ad5 was associated with increased infection."
In another blow to the prevention field, Connie Celum of the University of Washington, Seattle, revealed unexpected results from a study aimed at reducing susceptibility to HIV infection by treating preexisting infection with herpes simplex virus-2 (HSV-2). Infection with HSV-2, which causes genital ulcers, makes a person two to three times more vulnerable to HIV infection through sex. In a multi-country study involving more than 3000 people, Celum found that treatment with the anti-HSV-2 drug acyclovir did not reduce HIV transmission. Over the course of 18 months, 75 people who received acyclovir became infected with HIV versus 64 who received a placebo. "This is a surprising, disappointing, and important result," said Celum. "Many people thought this was going to be a slam dunk."
Celum said the problem wasn't linked to a failure to take acyclovir and that the treatment did reduce genital ulcers--although not as much as in earlier trials. That means intervention might work with a more powerful anti-HSV-2 drug or an effective HSV-2 vaccine, she said.
On a more positive note, two studies of thousands of HIV-infected pregnant women in several developing countries showed for the first time that anti-HIV drugs given to their babies could prevent transmission of the virus through breast milk. "The data are very exciting, but there are caveats," said Michael Thigpen of the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia, which sponsored one of the studies. Babies can develop resistance to the drugs, which can limit treatment options if they do become infected.
Some intriguing data came from studies of a new type of immune actor, discovered just 2 years ago, called Th17 cells. HIV targets and destroys CD4 white blood cells; Th17 cells are a subset of CD4 cells that secrete interleukin-17. Three labs reported that in monkeys and humans, destruction of Th17 cells in the gut make it "leaky," allowing gut microbes, or pieces of them, to flood into the bloodstream. The researchers contend that this turns up the immune system, "activating" CD4 cells that then prematurely die or become targets for HIV themselves. In one study, said Barbara Cervasi, a postdoc in Guido Silvestri's lab at the University of Pennsylvania, Th17 cells were profoundly depleted in the gastrointestinal tracts of HIV-infected people and SIV-infected macaques--species that both develop AIDS--but not in SIV-infected sooty mangabeys that suffer no harm from that virus. "People assume that high [HIV or SIV levels] lead to activation," said Silvestri. "What if it's the opposite and activation causes the problems?"
In the final session, George Shaw of the University of Alabama, Birmingham, reported that his group had sequenced the HIV envelope gene in 102 recently infected people. HIV-infected people carry many genetic variants of the virus, but a single one established an infection and dominated in 80% of the subjects, Shaw and co-workers found. Although other studies have shown that a "bottleneck" occurs in sexual transmission of HIV, allowing few viruses to infect, this is the first study to clarify just how few. Four other new studies have had similar findings, said Shaw.
Shaw, who hopes to discover and target HIV variants that are especially good at transmission, said this work is good news for vaccine researchers. "If all you've got to deal with is one virus," said Shaw, "surely it shouldn't be so difficult to develop a vaccine."
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