HIV Elite Controllers and the Future of AIDS Research

If left untreated, HIV will typically progress to AIDS; that is the general rule. However, a small subset of HIV-positive people is believed to be able to control HIV without ever progressing to AIDS—and without the use of antiretroviral drugs. These people, once called long-term non-progressors, are today commonly referred to as HIV elite controllers.

While experts had long considered this level of innate resistance a mystery, the bulk of evidence today suggests that specific genetic mutations confer to this "elite" control of HIV. As such, greater focus is being placed on determining if the same mechanisms can be mimicked in other people, with the ultimate aim of designing an HIV vaccine or some immunologic approach to controlling HIV drug without the use of drugs.

Defining Elite Control

Elite controllers are broadly defined as HIV-positive people who maintain undetectable HIV viral loads without the use of HIV drugs. Relieved of the burden of uncontrolled viral activity, elite controllers typically have well-preserved immune systems (as measured by the CD4 count), meaning their risk of opportunistic infection is considered low.

The figure can vary given that research often defines elite controllers differently. However, consensus is starting to emerge on a definition that "elite control is demonstration of multiple consecutive undetectable viral loads for at least 6 months or undetectable viral loads on at least 90% of measurements over 10 years."

This is an important distinction because we cannot confidently say those elite controllers will never advance in their disease or experience a sudden activation of viral activity. We have to assume that some of this population will.

Causes for Protection

Early studies were not successful in finding common traits and characteristics among elite controllers. It was not until the advent of genetic research and technologies that we were able to pinpoint commonalities among those with presumed elite control.

Among the key researchers, Harvard Medical School scientist Bruce Walker, M.D. was among the first to isolate the genetic differences in the make-up of this population, drawing evidence from a cohort of 1,500 elite controllers over the past decade.

In the normal immune system, specialized immune cells, called "helper" T-cells, recognize disease-causing viruses and "tag" them for neutralization. "Killer" T-cells then lock onto the virus at specific attachment points and effectively kill the virus.

However, HIV is able to adapt to the immune onslaught, mutating to prevent the "killer" cell attachment, while destroying the "helper" cells needed to signal the attack in the first place.

In his group's research, Walker was able to determine that the "killer" T-cells in the elite control group were able to function independently of "helper" T-cells. Furthermore, his team found that the "killer" cells were able to neutralize a broad diversity of HIV, not just a specific subset as is most often the case.

Since Walker's research was published, scientists have been able to isolate many of the genetic mutations found in the genome of the elite control population. Among them:

• The mutation of the FUT2 gene, which is found in 20 percent of the European population and is known to provide strong resistance to other types of virus.
• The presence of specialized genes called human leukocyte antigen B (HLA-B), which are found in a large proportion of elite controllers.
• The genetic mechanism which allows elite controllers to produce so-called broadly neutralizing antibodies (bNAbs) faster than non-elite controllers. bNAbs, by definition, are able to kill a broader variety of HIV. Typically, a non-elite-controller can take years to produce these cells, by which time HIV has already establish latent reservoirs which are largely impenetrable to attack. Elite controllers, by contrast, seem to be able to activate bNAbs almost immediately, preventing (or at least reducing) the establishment of latent reservoirs.

By identifying these genetic mechanisms, scientists hope to replicate the processes either through gene therapy, an immunologic vaccine, or a combination of biomedical approaches.

Downsides to Elite Control

Despite the optimism surrounding elite control and associated vaccine research, increasing evidence has shown that elite control comes at a price. When compared to non-elite-controllers on antiretroviral therapy (ART), elite controllers tend to have more than twice the number of hospitalizations, particularly from non-HIV-associated diseases that are known to disproportionately affect all people with HIV.

Even non-elite-controllers with detectable virus fared better, suggesting that ART manages to minimize some of the long-term chronic inflammation that we know can increase the risk and premature development of non-HIV-associated cancers, cardiovascular diseases, and neurological disorders.