How Cells Resist HIV Infection: New Clues

In the search for methods of curing HIV, some of our best leads have come from people with HIV or at risk of infection. For example, the cure of the “Berlin patient” with a stem cell transplant—one proof of concept that we will be able to eradicate HIV—hinged on selecting a donor who had a mutation in the CCR5 virus receptor, rendering those stem cells resistant to HIV infection. CCR5 was originally identified, and shown to mediate the natural resistance to HIV infection in some people despite repeated sexual exposures, through research funded by amfAR.

Dr. Mathias Lichterfeld

Dr. Mathias Lichterfeld

Now, writing in the journal Cell Host & Microbe, amfAR-funded scientist Dr. Mathias Lichterfeld and colleagues report on a normal cell protein that can indirectly inhibit HIV reverse transcriptase (RT), a crucial part of the virus that is targeted by RT inhibitor drugs such as AZT and tenofovir. This appears to be another clue as to how so-called “elite controllers” are able to suppress HIV without drug therapy.

Lichterfeld, working at Massachusetts General Hospital, along with colleagues from MIT, Harvard University, the City University of New York, and the Howard Hughes Medical Institute, took a lead from earlier research on HIV “dependency factors.” These are normal cell proteins that HIV has evolved to co-opt to further its own growth. But other normal host proteins can fight back, indirectly restricting HIV growth by inhibiting these factors.

The researchers homed in on a protein called p21. It had been known to suppress HIV in a variety of cells, but the mechanism of this effect was unknown. Lichterfeld’s group showed that p21 can indirectly block HIV RT by inhibiting CDK2, a host cell enzyme critical to HIV replication. (It may have more generalized anti-virus properties as well, as CDKs are also needed by human herpes viruses.)

Lichterfeld and associates also demonstrated that p21 is present in unusually high levels in the CD4+ T cells of elite controllers, a rare subset of HIV-positive individuals who naturally maintain undetectable levels of HIV without antiretroviral therapy. This is important as most previous studies of these individuals have focused on their immune systems, despite the fact that many are able to control the virus in the absence of strong anti-HIV immunity.

The potency of the p21 anti-RT effect was less than that of standard antiretroviral drugs. But, unlike those drugs, it avoids direct contact with the virus, and thus should be much less likely to lead to resistance. The authors conclude by stating that, “A better understanding of [this system] in elite controllers may help to induce a drug-free remission or functional cure of HIV-1 infection in broader patient populations.”

Dr. Laurence is amfAR’s senior scientific consultant.