Mechanisms for HIV persistence during effective treatment

Thesis (Ph.D.)--University of Washington, 2020Despite antiretroviral therapy (ART) that suppresses HIV replication to below the limit-of-quantification of commercial assays, small numbers of virions can often still be detected in the plasma, termed residual viremia (RV). The cells producing infectious RV must be eliminated to cure the infection. The dynamics of RV production was characterized by determining viral C2V5env sequences from longitudinally-derived plasma specimens, comparing RV sequences to those from replicating viruses in pre-ART plasma, in quantitative viral outgrowth assays (QVOA) of virus present in CD4+ T cells collected during ART, and in plasma from post-ART-interruption. Specimens from the time of acute infection and spanning more than 13 years of infection were examined from 3 participants in which ART was initiated after ~3 or more years of infection. Following ART-suppression for ~7 years, participants self-initiated ART-interruptions. RV was found to be composed of varying fractions (8-84%) of monotypic (i.e., clonally-derived) versus unique HIV genotypes that were most closely related to viruses produced throughout the pre-ART period, and these monotypic RV variants persisted for a median of 3 years (range:0.3-8.2) of ART-suppression. RV sequences were found to be identical to replicating viruses found during pre-ART and infectious variants induced in QVOA and rebound viremia (n=21/154 (14%)) across the 3 participants. The frequency of RV variants during ART was not always predictive of the composition to rebound viremia after ART-interruption. These findings are consistent with a dynamic “active” HIV reservoir during ART that can contribute to the rekindling of infection upon ART interruption. The persistence of monotypic RV variants over time suggests that the cells producing these virions either resist immune clearance or represent the occasional emergence from latency of only subpopulations of clonally proliferating, infected cell populations, which are only slowly cleared over time