Natural control of HIV-1 replication and long-term nonprogression: overlapping but distinct phenotypes.

With 133 million individuals infected with human immunodeficiency virus type 1 (HIV-1) worldwide, and with 12 million more individuals infected every year [1], the need for an effective HIV-1 vaccine has never been greater. With the recent failure of a T cell immunity vaccine to prevent HIV-1 infection, and with the suggestion that the vaccine actually increased the risk of HIV-1 infection in important population subgroups [2], the human immunodeficiency virus (HIV) research community is reexamining the mechanisms mediating both natural protection against HIV-1 in seronegative individuals exposed to HIV-1 and natural viral control among HIV-infected individuals. A critical reassessment of the goals of vaccination is also ongoing. The ideal HIV-1 vaccine should prevent HIV acquisition ; however, if this is not possible, reduction in the plasma HIV RNA level " set point " in vaccinated individuals is an important secondary goal. Indeed, HIV-1 transmission is uncommon when the plasma HIV RNA level of the source partner is !2000 copies/mL [3]. Reduction of the viral load set point as a goal of vaccination has spurred interest in a rare group of HIV-infected individuals who naturally control HIV replication in the absence of therapy. These untreated HIV-infected " elite controllers " (ie, patients with plasma HIV RNA levels of !50 cop-ies/mL) and " viremic controllers " (ie, patients with plasma HIV RNA levels of 50– 2000 copies/mL) are highly enriched for several host factors associated with T cell– mediated control, including the protective HLA B57 allele [4, 5]; these observations have motivated the development of T cell immunity vaccines for HIV-1. Would decreasing the viral load set point to the levels observed in HIV-infected elite and viremic controllers necessarily prevent clinical progression? Not all HIV controllers have long-term nonprogression. Many have assumed that HIV controllers represent a " functional cure " and are simply an elite subset of long-term nonprogressors (LTNPs; ie, patients who maintain CD4 + T cell counts in the normal range and AIDS-free survival indefinitely). However, as we and others have reported, the control of viral replication and the lack of clinical progression are really distinct clinical phenotypes. Some HIV-1 controllers experience significant CD4 + T cell count depletion and AIDS events, despite maintaining low to undetectable levels of vi-remia [6–10]. In this issue of the Journal, Okulicz and colleagues [11] reinforce this point by describing rates of disease progression among 25 elite and 153 viremic controllers in …