It became clear early in the HIV/AIDS pandemic that the course of the disease could vary widely. Indeed, while nearly all untreated HIVinfected individuals progress to AIDS and ultimately die from opportunistic infections or cancer, not all do. A small percentage of people exposed to the virus seroconvert, but do not seem to have progressive disease. Their CD4 Tcell counts and other measures of immune competence are maintained for decades without antiretroviral therapy. Among these longterm nonprogressors, one subgroup, called elite controllers, have unusually low levels of circulating virus (undetectable by standard clinical assays, despite ongoing lowlevel viral replication) and represent approximately 1 in 300 infected individuals. They are being studied intensively to discover how they are able to control their infection. A second group consists of individuals who engage in highrisk behaviors that repeatedly expose them to infection yet remain virus and diseasefree. Although evidence of prior HIV infection has been reported in such individuals, it is unclear whether these individuals were ever truly infected with infectious virus or were exposed to highly attenuated or defective strains unable e, an effect that acts early in progression to aiDS; l, acts late in aiDS progression; ?, plausible mechanism of action with no direct support. From O’Brien, S.J., and nelson, G.W.: Nat. Genet. 36:565–574. Reprinted with permission from Macmillan Publishers ltd. © 2004.
to successfully establish infection. In any case, study of these individuals is of considerable interest as it could provide a better understanding of how the host immune response might better control the virus and define what genetic factors might predispose to a protective host response. It might also provide mechanistic insights that could guide development of better vaccines.