The use of highly active antiretroviral therapy (HAART) in the treatment of HIV-1-infected individuals has provided a considerable amount of information regarding the dynamics of viral replication and has resulted in enormous advances in HIV therapeutics. The profound suppression of plasma viremia in HIV-infected individuals receiving HAART has resulted in a highly beneficial clinical effect and a dramatic decrease in the death rate attributable to AIDS. Nonetheless, the persistence of reservoirs of HIV, including latently infected, resting CD4+ T cells that can give rise to infectious HIV upon stimulation in vitro, has posed a sobering challenge to the long-term control or eradication of HIV in infected individuals receiving HAART. Although a recent study has demonstrated that the size of the pool of latently infected, resting CD4+ T cells can be markedly diminished with intermittent interleukin (IL)-2 and continuous HAART, complete eradication of HIV in infected individuals remains extremely problematic. Here, we discuss recent developments in studies of the latent reservoir of HIV in patients receiving HAART and implications for the long-term treatment of infected individuals and eradication of the infection.

With the advent of highly active antiretroviral therapy (HAART)—a treatment regimen consisting of a combination of at least three antiretroviral drugs and usually including at least one drug of the protease inhibitor class—for HIV-infected individuals, a greater degree of control of viral replication is now possible. In this regard, the widespread use of HAART has dramatically changed the clinical course of infection in many infected individuals and led to a substantial decline in the incidence of acquired immunodeficiency syndrome (AIDS) and AIDS-related mortality in the United States (1–5) and other developed countries (6–9). Furthermore, the study by Perelson et al. generated considerable optimism that HIV can be eradicated in infected individuals receiving HAART (10). This optimism was largely based on mathematical modeling of the kinetics of viral decay in the plasma of infected individuals shortly after initiation of HAART. However, the validity of this projection was predicated on the assumptions that viral replication is completely suppressed throughout that period of time and that no other unrecognized viral reservoirs with longer half-lives exist in infected individuals who are receiving HAART (10). Unfortunately, these assumptions have proven to be incorrect, and, thus, real concerns have arisen about whether complete eradication of HIV in infected individuals will ever be achievable using current HAART regimens (11–16). One of the most discouraging aspects of the feasibility of complete eradication of HIV from an infected individual is the persistence of latently infected, resting CD4 T cells carrying replication-competent HIV. These cells are likely a major reservoir for HIV, particularly when active virus replication is suppressed by HAART. In late 1997, three groups demonstrated independently that a pool of cells from which virus could be isolated persists in essentially all infected individuals tested who were receiving HAART for considerable periods of time (up to 3 years) and in whom plasma viremia was suppressed below levels of detection by the most sensitive assays (11–13). Pursuant to this sobering observation, intensive interest has been generated in the delineation of the nature of this viral reservoir, the process of its establishment, and the mechanisms of its persistence, as well as in strategies aimed at its containment and/or elimination.