Among the host cell proteins used by HIV when the virus infects cells is one called human transportin 3. When scientists halted production of that protein in host cells (blue), levels of HIV (red) in the cells were drastically reduced (lower panel) compared to infection under normal conditions (upper panel).

Viruses are needy. Equipped with few genes, they lean heavily on their host cells to help them successfully invade.

This is true of the human immunodeficiency virus (HIV), which has just nine genes that make only 15 proteins. With such a sparse molecular tool kit, it is a wonder that HIV can wreak such havoc. But its ability to take over the very immune cells intended to protect us from disease is well known. An atlas of those host cell factors the virus hijacks would provide a deeper understanding of the virus, perhaps providing potential ways to thwart it.

In January, a team led by HHMI investigator Stephen Elledge of Brigham and Women's Hospital in Boston produced just such a roadmap. Writing in the journal Science, Elledge's team reported that HIV requires at least 273 human proteins, called HIV-dependency factors (HDFs), to do its molecular dirty work.

“This is a tremendous resource for the entire field of HIV research,” says Dan R. Littman, HHMI investigator and an HIV expert at New York University Medical Center. “It's been known for a long time that these host factors were out there, but there had never been a systematic approach to identify them. I don't think anyone could have imagined how many would turn up.”

The study greatly expands the number of known HDFs, painting a newly detailed portrait of the virus and its dependencies. Only 36 of the human proteins commandeered by HIV had been previously identified.

To produce the expanded catalog of HDFs, Elledge's group, which included postdoctoral fellow Abraham Brass and Harvard Medical School's Judy Lieberman, tapped newly available commercial libraries of what are known as small interfering RNAs. These genetic molecules can switch genes off, preventing them from making proteins. By turning off genes in human cells one by one and then observing whether HIV could establish itself and reproduce, Elledge's team plodded through 21,000 disrupted genes to isolate those the virus required.

“We were looking for any genes that HIV needs for its life cycle,” Elledge says, pointing out that the proteins those genes make have the potential to be drug targets.

Drugs now in use directly attack HIV, and they must be used in combination since the virus has evolved resistance to individual compounds, explains Elledge. Making drugs that target host proteins could bypass resistance; if a host protein the virus requires is disrupted, the virus would have to do much more to overcome the challenge than simply rearrange a few amino acids of genetic material. The new study reveals that many host proteins play coopted roles throughout the cycle of HIV infection—for example, helping the virus glom onto and enter cells, converting RNA to DNA, and creating new infectious particles.

Photo: Abraham Brass / Elledge lab

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