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."

Only viruses that have mutated escape mechanisms from immune pressures are able to survive, but the mutations come at the cost of other aspects of viral fitness, perhaps inhibiting entry into cells or integration into cell DNA. According to Stephen Migueles, a National Institutes of Health researcher, "about 90 percent of the elite controllers in our cohort carry these protective alleles." Kwon adds that many, but not all, controllers show an enriched presence of multiple copies of these alleles.

What has become clear from their research is that there is no single genetic pathway to controlling HIV; there likely are multiple routes, each with their own combination of genetic and environmental factors. Host genetics are neither a necessary nor sufficient factor in explaining how some people control HIV. Migueles calls it "an important clue," but not the final answer to the question. The researchers hope that as the number of controllers enrolled in studies increase, so, too, will the power to detect specific genes and combinations thereof that affect the immune system's ability to control HIV.

CD8 T cells are the most important immune factor in reining in HIV. Migueles has found that for those who control the virus their CD8 T cells of are both quantitatively and qualitatively different from those who follow the typical course of disease progression. Not only do controllers have more CD8 T cells, each cell produces greater quantities of perforin and granzymes, which stimulate apoptosis, or cell death. "The capacity of these cells to kill is 40 percent greater," he says.

The role of inflammation

At the University of California, San Francisco (U.C.S.F.), a different group of researchers is investigating the role of inflammation and immune activation in HIV disease progression. Their hypothesis draws on the observation that sooty mangabeys (monkeys) infected with the simian immunodeficiency virus (SIV)—a pathogen thought to be the ancestor of HIV—have a high viral load but low immune activation. They do not progress to disease and live a normal life span comparable with animals not infected with SIV. But if you put that same virus into a rhesus macaque, the monkey's immune system reacts similarly to that of humans; there is severe depletion of CD4 T cells and progression to AIDS, explains U.C.S.F. researcher Peter Hunt. "The difference between these two scenarios is high levels of immune activation. We are not just talking about the T cells and B cells that are specific for HIV or SIV, we are talking about the vast majority of all immune cells in the body. Over 60 percent of their CD8 T cells are activated. This is profoundly unusual; usually we see about 10 percent activation in an individual who is not infected with HIV."

"The height or extent of immune activation seems to be a strong predictor of how rapidly people progress to HIV disease," Hunt says. Elite controllers have significantly lower levels of immune activation. Correspondingly, controllers with the highest level of immune activation have the lowest levels of CD4 counts. "We think that the majority of HIV controllers, while they are able to control virus replication, still have abnormal levels of inflammation," he adds. "The very small amount of virus that they harbor really drives a lot of inflammation. That is not without consequences. Inflammation has long been thought to play a role in cardiovascular disease and accelerating the aging process."

"As a field, we are starting to grapple with premature aging in the HIV-infected population, even in patients who are on therapy—their immune systems largely look like someone whose immune system is many years older," Hunt notes. "People are commonly getting cardiovascular disease and cancers normally associated with the aging process, just at earlier ages," he says. 

Hope for a vaccine
One possible implication of this line of research is the development of an HIV vaccine. Traditional vaccines stimulate the immune system ahead of time, preparing it to respond to a pathogen to which it has not yet been exposed. Vaccines often generate a higher response level than does natural exposure to the pathogen, to better fight off the invader.

But if a key issue with HIV disease is an overly stimulated inflammatory immune response, then perhaps the goal of a preventive vaccine should be to dampen rather than heighten an immune reaction. This stands vaccinology on its head and raises all sorts of new complications for research.