HIV-1 Reservoir Persistence and Decay: Implications for Cure Strategies

Abstract

Purpose of review: Despite suppressive antiretroviral therapy (ART), a viral reservoir persists in individuals living with HIV that can reignite systemic replication should treatment be interrupted. Understanding how HIV-1 persists through effective ART is essential to develop cure strategies to induce ART-free virus remission.

Recent findings: The HIV-1 reservoir resides in a pool of CD4-expressing cells as a range of viral species, a subset of which is genetically intact. Recent studies suggest that the reservoir on ART is highly dynamic, with expansion and contraction of virus-infected cells over time. Overall, the intact proviral reservoir declines faster than defective viruses, suggesting enhanced immune clearance or cellular turnover. Upon treatment interruption, rebound viruses demonstrate escape from adaptive and innate immune responses, implicating these selective pressures in restriction of virus reactivation. Cure strategies employing immunotherapy are poised to test whether host immune pressure can be augmented to enhance reservoir suppression or clearance. Alternatively, genomic engineering approaches are being applied to directly eliminate intact viruses and shrink the replication-competent virus pool. New evidence suggests host immunity exerts selective pressure on reservoir viruses and clears HIV-1 infected cells over years on ART. Efforts to build on the detectable, but insufficient, reservoir clearance via empiric testing in clinical trials will inform our understanding of mechanisms of viral persistence and the direction of future cure strategies.

Keywords: Cure; HIV-1 reservoirs; Persistence; Viral rebound.

Fig. 1

Dynamics of the HIV-1 reservoir following ART initiation. A Schematization of three measures of the proviral reservoir size plotted over time. “Total proviral DNA” corresponds to quantitative measurements of any proviral genomes, which are generally stable overtime. Methods that can differentiate defective from intact proviruses like IPDA and Q4PCR have shown relative stability of rthe defective pool, but a gradual decline in the intact proviral reservoir (red line). B Multiple forces that impact the size of the intact (filled color circles) and defective (white circles) proviral reservoir have been identified and/or postulated. Forces that expand population size are listed on top and forces thought to cause decay of the intact reservoir shown on bottom. C With time on suppressive ART, cells harboring intact proviral populations decrease in total number and become more clonal, as indicated by the expansion of certain clones (e.g., red clone) and loss of others (e.g., yellow clone). Figure created with BioRender