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

Abstract

Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of treatment and to identify cells replenished by ongoing replication. Decay rates of subsets of latently HIV-infected cells paradoxically decreased with time since establishment, reflecting heterogeneous lymphocyte activation and clearance. Residual low-level replication can replenish cellular reservoirs; however, it does not account for prolonged clearance rates in patients without detectable viremia. In patients receiving potent antiretroviral therapy, the latent pool has a heterogeneous and dynamic composition that comprises a progressively increasing proportion of stable lymphocytes. Eradication will not be achieved with complete inhibition of viral replication alone.

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

“…However, cellular activation reverses this latent state, allowing HIV-1 transcription and subsequent production of replication-competent virus (1)(2)(3)(4)(5). This small but stable latent reservoir necessitates life-long ART (7)(8)(9) and is a major barrier to curing HIV-1 infection. One proposed strategy for eliminating the latent reservoir is to pharmacologically stimulate HIV-1 gene expression in latently infected cells, rendering these cells susceptible to cytolytic T lymphocytes or viral cytopathic effects (10).…”

Characterisation, Evaluation and Clinical Significance of Latent HIV-1 Reservoirs and Therapeutic Strategies for HIV Eradication

“…Following this, slow viral decay, with a half life of between 39 and infinite weeks, reflects the release and clearance of HIV contained within the latently infected lymphocyte reservoir -the third and fourth decay phases of plasma HIV decline [89][90]. However, through the use of low copy viral load assays [91], most (80%) patients on HAART treatment have detectable persistent viraemia [92][93].…”

Exploring HIV latency using transcription profiling

“…Latent HIV has been primarily found in long-lived memory CD4 + T cells, which can survive for decades and expand the viral reservoir by cell proliferation [8][9][10][11] . These latently infected cells are considered to be the main barrier to HIV eradication 4 and their reactivation in vivo likely contributes to sustained immune activation observed during suppressive ART 12 .…”