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HIV vaccine failure explained?

Failed vaccine makes immune cells easier to infect in culture.

The STEP trial was halted after the vaccine failed to protect participants against HIV Credit: Punchstock

Researchers have suggested that an experimental vaccine against AIDS might have failed in part because it made some people's immune cells more vulnerable to HIV infection.

The team, led by Eric Kremer of the University of Montpellier in France, examined why people participating in the STEP vaccine trial who had previously been exposed to a cold virus, adenovirus 5, seemed more likely to become infected with HIV-1 than those who hadn't been exposed to the virus (see 'HIV vaccine may raise risk'). The trial was halted last September.

Because the STEP vaccine's backbone was made from a modified version of adenovirus 5, some researchers had speculated that it might be recognized by pre-existing antibodies in people who had previously been infected with this virus and eliminated from the body before an immune response to HIV-1 could develop.

But Kremer and his colleagues found that when antibodies to adenovirus 5 were combined with the vaccine backbone in a culture dish, they triggered a pathway that causes the activation of certain immune cells called T cells, which are targeted by HIV in their active state. In cell culture, T cells succumbed to HIV-1 infection three times more quickly than did those in a mixture that lacked adenovirus 5 antibodies, the researchers report. Their results, they suggest, show how injecting an adenovirus-5-based vaccine into people with adenovirus 5 antibodies could have created a "chronic permissive environment for HIV-1 infection"1.

The findings, explains Warner Greene, the director of the Gladstone Institute of Virology and Immunology in San Francisco, who was not involved in the work, suggest that HIV-1 "encounters a singularly target-rich environment favouring successful HIV transmission" in people who have previous exposure to adenovirus 5.

It ain't necessarily so

But many researchers are yet to be convinced that the new work explains what went wrong in the original trial. All of the group's experiments were done in culture dishes, and did not use cells or antibodies taken from individuals who were actually involved in the STEP trial.

"I think that it outlines a very interesting hypothesis that might explain some of the STEP data," says Larry Corey, leader of the HIV Vaccine Trials Network, which conducted the STEP trial. But he cautions, "One should recognize that the data presented are still largely in vitro and that further experiments to define whether this occurred among vaccinees in STEP need to be done."

In addition, as immunologist Nina Bhardwaj of New York University points out, the real-life relevance of a threefold increase in infection rates is uncertain. "I'm not sure what that means in vivo, and I wonder if it's a really huge difference," she says.

Jonathan Yewdell of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, says he is "dubious that this mechanism plays an important role in the HIV trial findings," because the events that it suggests make cells more vulnerable to HIV are probably "too transient to account for infections occurring weeks after vaccination".

"They're building on a series of reasonable hypotheses, but there are lots of alternative ways this could be happening," says Jeffrey Ravetch of the Rockefeller University in New York.

But the study is nonetheless a valuable attempt to try to make sense of the STEP trial results, Ravetch believes. "It's a very important exercise," he adds. "You have to try to understand what went wrong so you can design the next [vaccine] with that information in mind."

Credit: Punchstock


  1. Perreau, M., Pantaleo, G. & Kremer, E. J. J. Exp. Med. doi:10.1084/jem.20081786 (2008).

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Check Hayden, E. HIV vaccine failure explained?. Nature (2008).

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