amfAR, The Foundation for AIDS Research

Controlling HIV, Naturally

By Jeffrey Laurence, M.D.

April 9, 2008—Human diseases rarely, if ever, kill 100 percent of their sufferers. Even with a highly malignant cancer of the pancreas or a virulent virus such as rabies, some survivors will always emerge, providing clues to the means by which the body—even without the aid of drug treatment—can conquer an astonishing array of disorders. For HIV, this sort of “experiment of nature” is found in the so-called elite controllers—HIV-infected individuals able to ward off symptoms of infection, maintaining very low viral loads and high T-cell counts without taking anti-HIV drugs. amfAR researchers, writing in the March issue of the prestigious journal Nature Medicine, offer insights into just how this might happen, and how the good fortune of these “elite” few might be translated into treatments for others.

amfAR fellow Nicolas Chomont, Ph.D., working with amfAR grantees Jean-Pierre Routy, M.D., and Elias Haddad, Ph.D., at the University of Montreal, notes that while the vast majority of infected people relentlessly lose T cells as virus levels increase, some HIV-positive individuals—fewer than 1 in 100—can maintain T-cell numbers and low viral loads without anti-HIV medication for at least nine years after infection. The key difference in these elite controllers appears to lie with a special type of CD4+ T cell called the central memory cell, or CM. Compared with HIV-positive individuals who require constant antiretroviral treatment to limit virus production, or even healthy HIV-negative individuals, the CM cells of elite controllers are highly resistant to a variety of persistent immune stimuli that kill CM cells in other people. In particular, immune activation occurring in response to new infections, thought to kill many T cells from HIV-positive individuals, does little harm to the CM cells of elite controllers.

In the Nature Medicine article, the authors show that one pathway responsible for this CM resilience involves the FOXO3a protein. The University of Montreal researchers drew blood samples and found that artificially silencing FOXO3a in test-tube experiments, using a range of gene therapy techniques, extended the life of CM cells from HIV-positive individuals on drug therapy to a length of time similar to that of CM cells from elite controllers.

Defining exactly what is different about FOXO3a-related activity in the CM cells of elite controllers requires further study. But the work of Chomont, Routy, Haddad, and colleagues suggests that drugs capable of inhibiting FOXO3a might facilitate the maintenance or reconstitution of a more effective immune system in HIV-positive individuals. Dr. Haddad said in a March Toronto Globe and Mail article that these insights derived from HIV research could also have broad benefits for many other disorders, including cancers and other viruses.

Dr. Jeffrey Laurence is amfAR’s senior scientific consultant.