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.