Xiao-Fang Yu in his laboratory

The Mystery of Vif

By Jim Schnabel • Photo by Chris Hartlove

The AIDS-causing retrovirus HIV is a marvel of insidious efficiency. With a toolkit of just 19 different proteins, it easily thwarts the defenses of its vastly more complex H. sapiens hosts by infiltrating the very immune cells that should attack it. But HIV’s simplicity also means that its secrets won’t long withstand scientific scrutiny.

“After three decades of work, we’ve learned a lot about this retrovirus,” says Xiao-Fang Yu, MD, DSc, a professor in the Bloomberg School’s W. Harry Feinstone Department of Molecular Microbiology and Immunology. Yu is the senior author of a report in Nature in January that reveals a key detail of one of HIV’s most important survival strategies—a strategy that may soon be blockable with drugs.

The new finding concerns the HIV protein Vif (viral infectivity factor), a sort of bodyguard molecule that the virus needs to thrive and spread.

Xiao-Fang Yu’s latest discovery involves a “bodyguard” molecule for HIV called Vif and its partner in crime, the CBF- protein. Stop the pair from interacting, and you weaken HIV.

A decade ago, scientists discovered that human cells normally contain antiretroviral enzymes, known as APOBEC3 enzymes, that can bind to retroviral genes and mutate them destructively—except when Vif is present. As Yu and his colleagues reported in Science in 2003, Vif shields HIV by cleverly co-opting several normal proteins within infected cells, and using them to form a ubiquitin ligase—a complex enzyme that marks APOBEC3s for destruction by the host cell’s own housekeeping systems.

In the new study, Yu and his students discovered that Vif can coordinate this counterattack only with the added assistance of a host-cell protein called CBF-. “When we blocked CBF-’s interaction with Vif, we removed nearly all Vif’s ability to thwart the relevant APOBEC3 enzymes,” Yu says.

A key point for drug development purposes is that CBF- uses one part of its structure for binding to its normal protein partner in cells, and a different part for binding to Vif. Thus, it should be possible to block the Vif-CBF- interaction without disrupting CBF-’s normal function. Drug companies are already knocking on Yu’s door.

CBF- normally works in cells as a transcription factor that enhances the expression of certain genes, and research in the 1990s showed that two other viruses use this basic functionality of CBF- to enhance their own replication within infected cells. “It’s intriguing to see that CBF- has yet another pro-viral function, this time with HIV,” says Nancy Speck, a professor of cell biology at the University of Pennsylvania who did much of that earlier CBF- research.

Yu thinks it’s possible that CBF- serves as HIV’s partner in crime on yet another level, since in immune cells its job as a transcription factor effectively makes it a regulator of the broad immune response. “It’s easy to imagine that HIV might be co-opting CBF- in one way to combat APOBEC3s, and in another way to manipulate immune cell activity so as to benefit its own replication and survival,” he says.

Existing anti-HIV drugs can hold the virus at bay, but generally can’t remove it from the body. If Yu’s suspicion proves correct, then fully blocking Vif’s subversions of CBF-βmight at last enable the eradication of the virus.

“It’s an interesting hypothesis, and a testable one,” says Speck.