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What Makes HIV Tick?

Using cutting-edge molecular techniques, researchers identified more than 250 human proteins involved in HIV replication, raising the prospect of new therapeutic targets.

Most antiretroviral agents target HIV proteins rather than cellular factors. Understanding which host factors HIV requires for replication might lead to new targets for drug development. Now, researchers in Boston have used a powerful new technique to determine the cellular proteins necessary for HIV reproduction.

The researchers used pools of small interfering RNAs to disrupt the cellular expression of >21,000 human genes, one at a time, and measured the effect on HIV replication. They identified 273 cellular proteins on which HIV depends to complete its life cycle. Only 36 of these so-called HIV dependency factors (HDFs) had been found previously. Many HDFs were expressed at higher levels in immune cells — which are targeted by HIV — than in other types of cells. The investigators examined the mechanisms by which HIV interacts with several HDFs identified by this approach; these proteins were found to have roles in viral entry, integration, and transcription.

Comment: HIV is the most intensively studied human virus in history, yet we have barely scratched the surface in understanding how it interacts with our cells. This exciting study shows that HIV depends on many host proteins to replicate; future research will undoubtedly explicate the mechanisms by which HIV interacts with these cellular factors.

A potential clinical implication of the present findings is that drugs targeting these proteins may have therapeutic benefit. As an editorialist notes, because human proteins change more slowly than the virus under drug-selection pressure, HIV should have more difficulty escaping from agents that interfere with cellular targets. However, the difficulty in developing resistance is relative, not absolute. For example, HIV can evolve to become resistant to maraviroc, a drug that targets the human CCR5 protein. Another cautionary note: Some drugs that inhibit cellular targets will be quite toxic to the human host. However, pharmaceutical companies have successfully grappled with this challenge in developing most of our currently available medications. Even if this study does not lead directly to the development of new therapeutic agents, it has deepened our understanding of the mechanisms of HIV replication and the intricate and complicated dance between virus and host.

— Rajesh T. Gandhi, MD

Published in Journal Watch Infectious Diseases January 16, 2008

Citation(s):

Brass AL et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 2008 Jan 10; [e-pub ahead of print]. (http://dx.doi.org/10.1126/science.1152725)

Cohen J. HIV gets by with a lot of help from human host. Science 2008 Jan 11; 319:143.

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