Asymmetric division of activated latently infected cells may explain the decay kinetics of the HIV-1 latent reservoir and intermittent viral blips

Abstract

Most HIV-infected patients when treated with combination antiretroviral therapy achieve viral loads that are below the current limit of detection of standard assays after a few months. Despite this, virus eradication from the host has not been achieved. Latent, replication-competent HIV-1 can generally be identified in resting memory CD4+ T cells in patients with “undetectable” viral loads. Turnover of these cells is extremely slow but virus can be released from the latent reservoir quickly upon cessation of therapy. In addition, a number of patients experience transient episodes of viremia, or HIV-1 blips, even with suppression of the viral load to below the limit of detection for many years. The mechanisms underlying the slow decay of the latent reservoir and the occurrence of intermittent viral blips have not been fully elucidated. In this study, we address these two issues by developing a mathematical model that explores a hypothesis about latently infected cell activation. We propose that asymmetric division of latently infected cells upon sporadic antigen encounter may both replenish the latent reservoir and generate intermittent viral blips. Interestingly, we show that occasional replenishment of the latent reservoir induced by reactivation of latently infected cells may reconcile the differences between the divergent estimates of the half-life of the latent reservoir in the literature.

Post-treatment control of HIV infection

“…As shown in ref. 38, the combined effect of both drug classes can be represented by the overall treatment effectiveness, «, where 0 ≤ « ≤ 1, and « = 1 is 100% effective therapy. When treatment is stopped, drug efficacy « = 0.…”

“…As in previous modeling work, we assume that the fraction of infections that result in latency α L = 10 −6 and the death rate of these cells is d L = 0.004 d −1 (38). The results in Archin et al (40) suggest that βα L , where β is the mass-action infection rate constant, is of the order of 10 −14 mL per cell per d, and our values of β (41, 42) and α L (SI Appendix, Table S1) are consistent with this estimate.…”

Viral dynamics of an HIV model with latent infection incorporating antiretroviral therapy

“…Figure  shows the PRCCs results for each input parameters. The sign of the PRCCs indicates that the input parameter has a positive or negative [4,11,12,20] effect on the corresponding output. From Figure , we observe that parameters k, N , and λ have a positive effect on the size of H  and H  (|PRCC| > .), while the parameters n p and n rt have a negative effect, and we also find that the parameters k, N , and r have a positive effect on the size of R  -, while the parameters n p , n rt , d T , and c have a negative effect.…”

Reduced evolutionary rates in HIV-1 reveal extensive latency periods among replicating lineages

“…To independently investigate our phylogenetic findings, we expanded a previous dynamic pathogen-host model [26,27] by tracking viruses that have cycled through a Figure S1). Taxa are labeled P for plasma-derived virus and R for resting CD4+ T cell provirus.…”