HIV controllers: an untapped source of clues to overcoming HIV infection.

The goal of developing an effective AIDS vaccine to provide sterilizing immunity remains elusive; protection from disease progression but not protection from infection has been achieved in animal models. Current AIDS vaccine strategies are thus focused on protection from disease progression as a goal for first-generation HIV vaccines for humans. As a strategy to curtail the global epidemic, there is reason to believe that the epidemic would start to decline even if immunized persons were to become infected, as long as viral load could be durably sustained at levels that would make HIV transmission and disease progression much less likely. A reasonable upper-limit target level of plasma viremia for such vaccines would be less than 2000 RNA copies/mL, a level at which the probability of transmission and disease progression is markedly reduced. Moreover, if one could use immune-based therapies to achieve this level of control in persons already infected, the same benefits would accrue on an individual and population level.

Remarkably, there exists a small group of individuals who appear to survive without any adverse consequences from their HIV infection. These persons, who have been given the rather unfortunate designation "elite controllers," represent less than one-half of 1 percent of persons infected with HIV. They are able to keep the virus in near-total check, which means that they are still infected but the virus is somehow prevented from growing rapidly in their bodies and inflicting damage. How does this happen? We don't know! As incredible as this seems, we still do not understand the most fundamental ways in which these persons are able to beat the odds and live for years--some now for more than 25 years and counting--without developing AIDS. And they do this without ever needing antiretroviral medications.

Understanding how viral control is achieved in these HIV controllers is likely to be critical to the process of vaccine development. And yet, it is poorly understood in part because of limitations in identifying sufficient subjects with sufficient volumes of samples to study, and in part because comprehensive studies of both the virus and the body's immune response have not been performed on these same subjects. Becoming familiar with the mechanisms of durable viral control will require comprehensive viral and host genetic data in conjunction with functional data on the innate and adaptive immune responses, something that is yet to be attempted.

With substantial seed funding from the Mark and Lisa Schwartz Foundation, we have initiated a comprehensive and collaborative large-scale study to attempt to break the code of how this remarkable state of "elite control" is achieved, but this will require very large numbers of such individuals. Approximately 1 patient in 300 is an elite controller, able to control HIV-1 replication to less than 50 RNA copies/mL without the need for antiretroviral medications. Our data thus Far indicate that host genes play an as yet poorly defined role. It also appears that preferentially targeting certain HIV proteins by the immune response may play a role. However, none of the parameters identified thus far has high predictive power for this outcome. Nevertheless, it is now possible to define the genetic basis of this outcome through new techniques that have been established in relation to the Human Genome Project, which allows for rapid and comprehensive identification of gene sequences that are associated with certain disease states.

To search for novel human genetic factors that influence HIV viral load, we will conduct what is called a "whole genome association scan" (WGAS) on persons at the extremes of the amount of HIV levels in the blood, under the hypothesis that host genetic factors influence immune responses and durable suppression of HIV infection. Such association studies, applied to other diseases such as macular degeneration, have successfully identified genes that have an important role in causing disease. Because the genetic screen is not biased towards any gene or pathway of known biologic function, this approach has the greatest opportunity of distinguishing factors previously unidentified as being important in viral control. Once a causal gene is identified, this information will provide immediate insight into host genetic factors and immunologic pathways that regulate HIV control.

The WGAS will use more than 650,000 genetic signatures called single-nucleotide polymorphisms (SNPs) in 1000 elite controllers, 1000 viremic controllers, and up to 3000 age/sex/ethnicity-matched control individuals with progressive viremic HIV-1 infection. Identification of a gene that influences host immune responses and viral load, as well as its mechanism of action, will have immediate practical applications not only for development of an effective AIDS vaccine but also for identification of potential new therapeutic targets.

The key to the success of this project is the ability to find the persons that fit these highly specific criteria. We are trying to locate at least 1000 elite controllers and 1000 viremic controllers--the latter with persistent viral loads (for greater than 1 year in the absence of therapy) of 50 to 2000 RNA copies/mL. Thus far, through collaboration with scientists, health care workers, AIDS service organizations such as The Center for AIDS Information & Advocacy, and patients themselves, we have identified more than 150 elite controllers and a similar number of viremic controllers. The success of this project will depend on our ability to find the additional necessary patients. If the true frequency is 1 in 300 and there are close to one million HIV-infected persons in the US, then there are at least 3000 persons that fit the elite controller category alone. Our challenge as a group is to recruit as many of these persons as possible, as they offer a unique and untapped resource that can provide critical clues to ending the HIV epidemic.

Bruce D. Walker is Director of Partners AIDS Research Center at Massachusetts General Hospital at Harvard Medical School in Charlestown, Massachusetts.