Researchers have discovered how HIV is able to reproduce within a type of immune cell called a macrophage and how it evades many of the most common antiretroviral (ARV) therapies. This new finding was published December 10 in The Journal of Biological Chemistry and detailed in a release from the University of Rochester in New York.

Macrophages serve as one of the first lines of defense against viruses, bacteria and other microbes. The Greek term macrophage translates into English as “big eater,” which describes their function—to engulf an infectious organism and then present small bits of it to other immune cells. This helps provoke a strong response against the invaders. HIV, however, is able to hijack macrophages and use them to infect other cells.

Baek Kim, PhD, from the University of Rochester, has been studying macrophages for more than 15 years in hopes of understanding fully how HIV is able to hijack the molecular machinery of macrophages and turn it to the advantage of the virus. Now, he and other researchers at the University of Rochester and Emory University in Atlanta, report that they've figured it out.

It turns out that HIV is able to utilize more than one type of molecular “tool” in order to reproduce inside cells. It is widely known that HIV commonly uses a molecule called deoxynucleoside triphosphate (dNTP) to build strings of HIV DNA that turn most other immune cells into virus factories. This molecule, however, is in short supply inside macrophages. For this reason, HIV's ability to replicate inside macrophages has remained somewhat of a mystery. What Baek and his team discovered, however is that HIV can turn to another type of molecule, called ribonucleoside triphosphate (rNTP), when dNTP has been knocked out.

“The virus would normally just use dNTP, but it's simply not available in great quantities in the macrophage. So HIV begins to use rNTP, which is quite similar from a chemical perspective. This is a surprise,” Kim said. “The virus just wants to finish replicating, and it will utilize any resource it can to do so.”

The findings will need to be confirmed by further research, and it will take some time to determine whether they can be applied to treat or prevent new infections. However, one of Kim's partners in this research, Raymond Schinazi, PhD, from Emory says this finding could have significant implications for both HIV treatment and prevention.

Many ARVs target the molecule dNTP. Kim's finding that the virus can also use rNTP means that such drugs may not effectively target macrophages and shut down viral reproduction there. Since macrophages are the first cells that HIV encounters, current ARVs might not be able to effectively block infection. Likewise, once a person is infected, the macrophages that line the gut and inhabit lymph nodes might also be resistant to the effects of typical ARVs.

“This significant breakthrough was unappreciated prior to our paper. We are now exploiting new [ARV] drugs jointly based on this novel approach that are essentially not toxic and that can be used to treat and prevent HIV infections,” Schinazi said.