Learning from Persistent Viremia: Mechanisms and Implications for Clinical Care and HIV-1 Cure

Abstract

Purpose of review: In this review, we discuss what persistent viremia has taught us about the biology of the HIV-1 reservoir during antiretroviral therapy (ART). We will also discuss the implications of this phenomenon for HIV-1 cure research and its clinical management.

Recent findings: While residual viremia (RV, 1-3 HIV-1 RNA copies/ml) can be detected in most of people on ART, some individuals experience non-suppressible viremia (NSV, > 20-50 copies/mL) despite optimal adherence. When issues of drug resistance and pharmacokinetics are ruled out, this persistent virus in plasma is the reflection of virus production from clonally expanded CD4⁺ T cells carrying proviruses. Recent work has shown that a fraction of the proviruses source of NSV are not infectious, due to defects in the 5'-Leader sequence. However, additional viruses and host determinants of NSV are not fully understood. The study of NSV is of prime importance because it represents a challenge for the clinical care of people on ART, and it sheds light on virus-host interactions that could advance HIV-1 remission research.

Keywords: Clonal expansion; Defective provirus; HIV-1 integration; Nonsuppressible viremia; Residual viremia; Virus production.

Fig. 1

Characteristics of persistent HIV-1 viremia during effective antiretroviral therapy. A Distribution of HIV-1 RNA levels in plasma among people on ART; each bar represents a range of HIV-1 RNA copies/mL; RV, residual viremia; NSV, non-suppressible viremia; SCA, single copy assay; limit of detections of most clinical assays are indicated by dashed lines. B Example of an individual developing NSV after years of undetectable viremia; standard ART regimen and ART intensification and indicated by light and dark gray areas, respectively. C Representative simulated phylogenetic maximum-likelihood tree of HIV-1 sequences recovered from plasma virus (orange circles), viral outgrowth (purple circles), or proviral DNA (blue squares); boxes and arrows indicate large groups of identical sequences reflecting clonally expanded HIV-1-infected cells; example clones of interested are indicated by numbers: clone 1 is replication competent but does not contribute to viremia; clone 2 is also infectious, it can be found in plasma, and it can be detected among infected cells; clone 3 is a predominant plasma variant, but it cannot be recovered by viral outgrowth. D Summary of virus and host factors that may favor only some infected clones to contribute to NSV. E Schematic of the potential response of a study participant with NSV to experimental interventions aimed at enhancing virus production and/or elimination of infected cells causing NSV; LRA, latency-reversing agent