INTRODUCTION
Human immunodeficiency virus type I (HIV-1) replicates in most untreated infected individuals at high levels throughout the infection. This includes the clinical quiescent phase, and levels of this active viral replication directly correlate with disease progression rates and survival.1-4 Combination therapeutics for HIV-1, or highly active antiretroviral therapy (HAART), has led to dramatic decreases in viral replication in vivo to below the clinical limits of detection (i.e., plasma HIV-1 ribonucleic acid [RNA] levels below 50 to 400 copies/ml, depending on the assay system used) and a drastic reduction in morbidity/mortality, at least in the developed world.5-7 These therapeutic modalities have completely altered the epidemic in many regions.
The era of HAART now allows for clearer investigations of classical questions in human retrovirology as well as for the generation of new clinical problems. In fact, mechanisms of viral latency and hidden or “cryptic” viral replication can now be addressed without the “noise” of active virally producing cells and high levels of cell-free virions,8 as virally suppressive HAART unveils viral persistence.After an individual is infected with HIV-1, replication of the virus occurs at a rapid rate. However, the half-life of virions in blood plasma seems to be within a time frame of hours.9 Initially, the great majority of viral replication occurs in activated, productively infected CD4+ T lymphocytes in peripheral blood as well as lymphoid tissue. After the initiation of HAART, there seems to be an initial phase of rapid decay of plasma viral RNA involving productively infected cells, followed by a second phase of decay in what is likely persistence of virus within more long-lived cells, perhaps tissue-bound macrophages.9,10 The final phase includes some loss of persistently infected cells, such as resting CD4+ T lymphocytes, but this decay period is prolonged and may require many decades of HAART-mediated viral suppression to accomplish.11,12
Effective HAART blocks the virus from infecting healthy CD4+ T cells, and the initial drop in HIV-1 levels in the peripheral blood reflects the life spans of cells that were infected before treatment was initiated. Based on the complex viral and cellular kinetics with slow decay of viral-infected cells in several phases, most HIV-1-infected individuals would require complete suppression of viral replication for years if one is even going to consider viral eradication.
It is critical to note that true viral eradication may be extremely difficult for many reasons (see below), including the finding that cells other than those in the immune system (e.g., kidney, heart) also seem to be infected at low levels with HIV-1 in vivo.1,13,14 Furthermore, this goal is hindered by several factors, including less than optimal treatment, HIV-1 infection in immunologically privileged sites, partial drug sanctuary compartments, in vivo “spikes” or “blips” of plasma viremia occurring in certain patients on virally suppressive HAART, and potential ongoing de novo cellular infections, secondary to local bursts of viral replication.15New therapeutic strategies toward possible viral eradication or at least long-term remission need to be fully investigated to rationally design novel antiretroviral approaches.
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