ELITE CONTROLLERS: The immune systems of perhaps 50,000 Americans somehow control HIV for long periods of time such that these people don't get sick from the virus.
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More than half a million people in the U.S. have died from HIV infection, and more than a million currently live with the virus, but a relative handful of people infected with HIV never get treatment for it and never get sick from it. The immune systems of this small population—perhaps 50,000 Americans—somehow control the virus for long periods of time. Of course, there is typically a bell curve of response to any disease, but figuring out how these people control the virus is one of the most vexing mysteries of the AIDS pandemic. Solving it might unlock new ways to prevent and treat HIV infection, and now several research teams are going after the answer.

Ten years after infection with HIV, a typical person has progressed to where tens if not hundreds of thousands of copies of the virus can be found in a single milliliter of their blood and more than three quarters of their CD4 immune cells are destroyed, if they have not started drug therapy.

"Long-term nonprogressors" is a category of persons whose disease progresses less rapidly than average. Researchers originally used the term broadly but now they have been able to tease out two subsets of patients within a hierarchy:

"Viremic controllers" are the next segment down the curve. After 10 years, one can find only 50 to 2,000 copies per milliliter of HIV in their blood; their CD4 count may be stable or may have declined, sometimes significantly. At the far end of the curve are "elite controllers," people whose immune system suppresses HIV below 50 copies per milliliter; their CD4 cells have not declined, even a decade or more after initial infection.

Studying HIV controllers, however, is difficult. Testing for HIV is not part of routine medical care; an estimated quarter to a third of those infected with the virus in the U.S. do not know they are carrying it; and many learn of their infection only when they suffer an opportunistic infection that is typical of advanced HIV disease.

Thus, controllers are likely to be disproportionately represented among those who do not know their HIV status. Other controllers have been put on therapy early, perhaps before they needed to be. Doctors and patients simply do not know enough about this type of response and where to refer these patients to participate in a study. And finally, privacy laws hamper communications between controllers who might otherwise help to push the research forward. All of these contribute to making it difficult to identify and study HIV controllers.

Their rarity became apparent in a recently published analysis of HIV-positive soldiers serving in the U.S. military. Elite controllers were just 0.55 percent of the 4,586 persons in the military cohort (viremic controllers made up 3.34 percent). This population offers perhaps the best natural history that scientists are likely to obtain, because all soldiers are regularly screened for HIV and all infections are identified fairly soon after they occur. 

It's in the genes
The virus carried by HIV controllers is less fit; it reproduces less rapidly than virus in people who do not control HIV as well, according to Douglas Kwon. It is not that these people were fortunate to become infected with a less fit virus but rather "the immune system drives it to a less fit variant," he adds. Kwon is part of the research team assembled by Howard Hughes Medical Institute investigator Bruce Walker of the Ragon Institute at Massachusetts General Hospital. They are analyzing the genes and immune function of HIV controllers, about 1,600 so far.

Host genes of the major histocompatibility complex (the genes that determine how mammals respond to pathogens) play a significant role in how the immune system responds to all pathogens. Several variants, such as the HLA B*5701 allele, have been associated with the pace of HIV disease progression in both controllers and "normals."