University of Rochester

In Review

For more than 15 years, Baek Kim, a professor of microbiology and immunology, has been fascinated by HIV’s ability to hide in the body. How can the virus take cover in a cell—the macrophage—whose very job it is to kill foreign cells?

New research by Kim and Raymond Schinazi, director of the Laboratory of Biochemical Pharmacology at Emory University’s Center for AIDS Research, has uncovered HIV’s novel mechanism for survival in a class of cells that typically provide the first line of immunological defense. Their research, published in the Journal of Biological Chemistry, indicates that HIV is able to exploit the unusual molecular makeup of macrophages to gain an often-overlooked foothold in the immune system.

The breakthrough may open up a new front in the battle against HIV, which infects more than 30 million people worldwide.

Kim’s and Schinazi’s finding may provide the basis for an unexpected tactic for stopping the virus, perhaps before HIV infection can take hold.

“If we have a drug that blocks HIV replicating in the macrophage, then we can use it as a preventive medication,” says Kim.

When HIV first enters the body—at least in cases of sexual transmission—it infects macrophages, white blood cells that Kim calls the “first defenders of our system.”

Normally, HIV uses dNTP—deoxynucleoside triphosphate, the building blocks for making the viral genetic machinery—to replicate, but those molecules are scarce in macrophages.

Instead they contain high levels of the closely related molecule rNTP—and HIV adapts to exploit that resource within the defensive cells, Kim and Schinazi found.

“This is a surprise,” Kim says. “The virus just wants to finish replicating, and it will utilize any resource it can to do so.”

When the team blocked the ability of the virus to interact with rNTP, HIV’s ability to replicate in macrophages was slashed by more than 90 percent.

“HIV replicates in the macrophage for months, for years—and then evolves to move on to T cells,” another form of immune cell, Kim says.

The 20 drugs currently used to combat HIV go after the infection when it’s already in the T cells. These are drugs “made to help already sick people, not to prevent infection,” Kim says.

With this new information about how HIV operates, it may be possible to “create a microbicide to stop the virus or limit its activity much earlier.”

Kim and his colleagues are already pursuing that possibility. There are some plant species—such as some wild mushrooms—that possess chemical compounds that protect them from viral replication using rNTP. One such substance, cordycepin, is an experimental compound derived from wild mushrooms that’s being tested as anticancer drug. Kim’s team is working with a pharmaceutical company to develop similar compounds that may stop HIV.

So far, they’re “very primitive” chemical compounds, Kim says, but he’s hoping they’ll lead to others that are more effective and less toxic.

By looking to other species that have developed such protections, he adds, it may be possible for researchers to find a way “to defend against HIV.”

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Additional reporting by Tom Rickey, associate director of research communications at the Medical Center.