Decelerating Decay of Latently Infected Cells during Prolonged Therapy for Human Immunodeficiency Virus Type 1 Infection

Abstract

Antiviral therapy induces a rapid drop in human immunodeficiency virus type 1 viremia, but the decline of virus levels decelerates over time. Mathematical modeling demonstrates that the source of residual virus production might be a single compartment of latently infected cells with an extended distribution of activation rates.The rapid initial decline of virus levels after the initiation of highly active antiretroviral therapy (HAART) reflects the decline of productively infected CD4 ϩ T cells (15,18,24). The slower second phase has been attributed to another cell population that produces fewer viruses initially but that has a slower turnover rate (17). Eventually, virus RNA becomes undetectable in patients with sustained suppression of virus replication. Occasional viral "blips" and the rebound of virus after discontinuation of therapy (5, 9), however, indicate the persistence of virus reservoirs even after 5 or more years of suppressive treatment (for a recent review on reservoirs see reference 21). As even the hypothetical persistently infected cell population should dwindle to a point of extinction in 2 to 3 years (17), the source of residual virus replication must be sought elsewhere. Finally, statistical analyses have shown that the observed decay of the virus level cannot be described in terms of a simple exponential decay ( Latently infected CD4 ϩ T lymphocytes have been shown to harbor replication-competent integrated provirus even after years of suppressive therapy (8,12,25). The pool of latently infected cells is established early during primary human immunodeficiency virus type 1 (HIV-1) infection (6), presumably by the reversion of productively infected memory CD4 ϩ T cells into the resting state (20). In vitro these cells can be induced to produce infectious virus, and activation has been shown to occur also in vivo upon encounter with the appropriate recall antigens (14) or by the administration of activating lymphokines (7). In patients with apparently complete suppression of HIV-1 replication by HAART, the source of rebounding virus after the cessation of therapy was identified as the latently infected cell pool (26). However, the exact contribution of this pool to the residual virus production during fully suppressive HAART has not been clarified. Here we present a mathematical model on the dynamics of latently infected cells and their impact on residual virus replication. We show that a decelerating decay might be an inherent characteristic of this system.Our goal was to model virus production by reactivated latently infected T cells after prolonged fully suppressive therapy when the initial major virus-producing population has already dwindled. This restricted goal allowed us to neglect much of the complexity of HIV-1 infection. We considered latently infected cells, L, which die at rate ␦ L L and which are reactivated at rate ␣L, and cells actively producing virus, T*, which arise by the reactivation of latently infected cells and which die at rate ␦T*. The generation of latently or product...

Effect of Treatment, during Primary Infection, on Establishment and Clearance of Cellular Reservoirs of HIV-1

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Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: Intrinsic stability predicts lifelong persistence

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A viral load-based cellular automata approach to modeling HIV dynamics and drug treatment

“…Recent studies have shown that a pool of latently infected cells is established during the primary phase of HIV infection (Bonhoeffer et al, 1997;Grossman et al, 1998;Havlir et al, 2003;Lafeuillade et al, 2000;Muller et al, 2002). These cells are infected cells in a resting state and can be activated after a long time of dormancy to produce infectious virus particles.…”