BioEd Online

One of HIV’s strengths — its ability to use human proteins to enter human cells or integrate with host DNA — may prove to be its undoing. Researchers have now identified over 250 of the human proteins that are needed by HIV to help it spread throughout the body, providing a treasure trove of potential HIV drug targets.

Antiviral drugs, which typically attack viral proteins, have had a huge impact on the quality and length of life of HIV-positive patients. But HIV mutates rapidly, so these drugs can quickly become outdated. And since HIV only makes 15 different proteins, there are limited viral targets for drug development.

Investigating which human proteins are used by HIV provides a different way of looking for new treatments. If drugs can turn production of those proteins down, without having too drastic an impact on the patient, then HIV could be stopped in its tracks. "If you could inhibit a host protein that is necessary for HIV progression, HIV would have to develop a new ability. And in the number games, that doesn’t happen," says Stephen Elledge, a geneticist at Harvard Medical School in Boston, Massachusetts. "That’s why host proteins could make tremendously good drug targets," he says.

Power in numbers

Before now, researchers had identified only a couple of dozen of the human proteins that are exploited by HIV.

To find more of these proteins, Elledge and his colleagues used RNA interference to block the expression of a single gene in each of some 21,000 pools of human cells — this created ‘knockout’ cells for practically every gene in the human genome. These pools of cells were then treated with HIV and examined for two signs of HIV progression: the presence of an HIV-protein called Gag on the surface of the human cells, and the ability of the cells to infect new, uninfected human cells.

Remarkably, 273 of the gene knockouts were lacking one or both of these signs of HIV progression, showing that the proteins encoded by those genes are important to HIV. Of these, only 36 had previously been implicated in helping HIV, the authors report in Science. "There are certainly lots of proteins that no one would have ever guessed are involved in HIV infection," says Elledge.

Paul Volberding, co-director of the Center for AIDS Research at the University of California, San Francisco, says that the study shows the power of genomics to help find medicinal targets. “The idea of using this approach to lead towards the development of novel therapeutics is very intriguing,” he says.

Self-harm

Martin Hirsch, also at Harvard Medical School, agrees that this may eventually spur new therapeutic approaches against HIV. But he says that there are worries about using human proteins as targets: drugs that interact with human proteins are also frequently toxic. The key is to find drugs that heal without causing too much harm. "Many previous investigators have gone this route over the past 20 years, with minimal success," he says.

Elledge suggests one way to minimize toxicity from these sorts of drugs might be to interfere with several of the proteins, without knocking any of them out completely. This might help to preserve the critical functions of these proteins for the patient, while wiping out a critical function for HIV. "The cell may not depend on these pathways for a single function, but the virus could."

The next step for Elledge and his colleagues is to figure out how these human proteins interact with HIV. They expect others to contribute to the process. “We really want the field to just take it and run with it,” says Elledge.