Limits on Replenishment of the Resting CD4+ T Cell Reservoir for HIV in Patients on HAART

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Abstract
Whereas cells productively infected with human immunodeficiency virus type 1 (HIV-1) decay rapidly in the setting of highly active antiretroviral therapy (HAART), latently infected resting CD4+ T cells decay very slowly, persisting for the lifetime of the patient and thus forming a stable reservoir for HIV-1. It has been suggested that the stability of the latent reservoir is due to low-level viral replication that continuously replenishes the reservoir despite HAART. Here, we offer the first quantitative study to our knowledge of inflow of newly infected cells into the latent reservoir due to viral replication in the setting of HAART. We make use of a previous observation that in some patients on HAART, the residual viremia is dominated by a predominant plasma clone (PPC) of HIV-1 not found in the latent reservoir. The unique sequence of the PPC serves as a functional label for new entries into the reservoir. We employ a simple mathematical model for the dynamics of the latent reservoir to constrain the inflow rate to between 0 and as few as 70 cells per day. The magnitude of the maximum daily inflow rate is small compared to the size of the latent reservoir, and therefore any inflow that occurs in patients on HAART is unlikely to significantly influence the decay rate of the reservoir. These results suggest that the stability of the latent reservoir is unlikely to arise from ongoing replication during HAART. Thus, intensification of standard HAART regimens should have minimal effects on the decay of the latent reservoir. Latently infected resting CD4+ T cells represent a stable reservoir for human immunodeficiency virus (HIV). When HIV-infected individuals are treated with highly active antiretroviral therapy (HAART), this latent reservoir decays slowly, with a half-life of up to 44 months. As a result, latently infected resting CD4+ T cells represent the major known barrier to eradication of HIV infection. Two factors are believed to contribute to the stability of the latent reservoir in the setting of HAART: replenishment by low-level viral replication and the intrinsic stability of resting memory CD4+ T cells. Unfortunately, it has not been possible to measure replenishment of this latent reservoir. In this study, we take advantage of a cohort of patients on HAART whose plasma virus consists largely of one (patient-specific) predominant plasma clone (PPC) that is grossly underrepresented in resting CD4+ T cells. We use the PPC as a label for ongoing viral replication by observing the accumulation of the PPC in resting CD4+ T cells over time in each patient. Analysis of the rate at which the PPC accumulates in resting CD4+ T cells allows us to quantitatively infer the maximum inflow of cells into the latent reservoir for HIV. Thus, we are able to provide the first quantitative constraint to our knowledge on the replenishment rate of the latent reservoir in the setting of HAART. Our results indicate that the rate of replenishment is very small and likely not a source of stability in the setting of HAART. These results have important implications regarding therapeutic options for purging the resting CD4+ T cell reservoir and curing HIV infection. Specifically, these results suggest that the intrinsic stability of latently infected resting CD4+ T cells, and not low-level viral replication, must be targeted therapeutically in order to achieve eradication of the latent reservoir.