Abstract
BackgroundIn the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-1 (HIV-1) rapidly decay to below the limit of detection of standard clinical assays. However, reactivation of remaining latently infected memory CD4+ T cells is a source of continued virus production, forcing patients to remain on HAART despite clinically undetectable viral loads. Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-1 infection. However, the mechanism underlying the long half-life of the latent reservoir is unknown. The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells.MethodsHere we use a mathematical model of T cell dynamics in the setting of HIV-1 infection to probe the decay characteristics of the latent reservoir upon initiation of HAART. We compare the behavior of this model to patient derived data in order to gain insight into the role of low-level viral replication in the setting of HAART.ResultsBy comparing the behavior of our model to patient derived data, we find that the viral dynamics observed in patients on HAART could be consistent with low-level viral replication but that this replication would not significantly affect the decay rate of the latent reservoir. Rather than low-level replication, the intrinsic stability of latently infected cells and the rate at which they are reactivated primarily determine the observed reservoir decay rate according to the predictions of our model.ConclusionThe intrinsic stability of the latent reservoir has important implications for efforts to eradicate HIV-1 infection and suggests that intensified HAART would not accelerate the decay of the latent reservoir.
Highlights
In the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-1 (HIV-1) rapidly decay to below the limit of detection of standard clinical assays
We extend elegant models of HIV-1 and CD4+ T cell dynamics previously described by Alan Perelson and Martin Nowak [28,32] to explore how low-level viral replication influences the observed decay of the latent reservoir in patients on HAART
While offering insight into the persistence of low-level viremia and the latent reservoir, the analysis presented in Kim and Perelson does not directly address two key clinical issues: (1) whether εHAART > εcrit in the typical HAARTtreated patient and (2) how the decay rate of the latent reservoir is affected by further increasing the efficacy of HAART when εHAART is already greater than εcrit
Summary
In the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-1 (HIV-1) rapidly decay to below the limit of detection of standard clinical assays. The two most reasonable mechanisms for maintenance of the latent reservoir in the setting of HAART are 1) replenishment by low-level viral replication [10,11,12,13,14,15,16,17,18,19,20] and 2) the intrinsic stability of latently infected cells (i.e. memory T cells) [8,9,21,22,23]. We have previously shown that the maximal rate at which new cells enter the reservoir in the setting of HAART is extremely low [27] These studies provide indirect evidence that intrinsic stability of memory T cells and not replenishment by ongoing viral replication is the major reason for the stability of the latent reservoir
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