Abstract
BACKGROUNDThe relative stabilities of the intact and defective HIV genomes over time during effective antiretroviral therapy (ART) have not been fully characterized.METHODSWe used the intact proviral DNA assay (IPDA) to estimate the rate of change of intact and defective proviruses in HIV-infected adults on ART. We used linear spline models with a knot at seven years and a random intercept and slope up to the knot. We estimated the influence of covariates on rates of change.RESULTSWe studied 81 individuals for a median of 7.3 (IQR 5.9-9.6) years. Intact genomes declined more rapidly from initial suppression through seven years (15.7% per year decline; 95% CI -22.8%, -8.0%) and more slowly after seven years (3.6% per year; 95% CI -8.1%, +1.1%). The estimated half-life of the reservoir was 4.0 years (95% CI 2.7-8.3) until year seven and 18.7 years (95% CI 8.2-infinite) thereafter. There was substantial variability between individuals in the rate of decline until year seven. Intact provirus declined more rapidly than defective provirus (P < 0.001) and showed a faster decline in individuals with higher CD4+ T cell nadirs.CONCLUSIONThe biology of the replication-competent (intact) reservoir differs from that of the replication-incompetent (non-intact) pool of proviruses. The IPDA will likely be informative when investigating the impact of interventions targeting the reservoir.FUNDINGDelaney AIDS Research Enterprise, UCSF/Gladstone Institute of Virology & Immunology CFAR, CFAR Network of Integrated Systems, amfAR Institute for HIV Cure Research, I4C and Beat-HIV Collaboratories, Howard Hughes Medical Institute, Gilead Sciences, Bill and Melinda Gates Foundation.
Highlights
The latent HIV-1 reservoir is established early in the course of infection and persists despite suppressive antiretroviral therapy (ART) [1,2,3,4]
The intact proviral DNA assay (IPDA) will likely be informative when investigating the impact of interventions targeting the reservoir
Individuals had been on suppressive ART for a median of 617 days (IQR 84–1369) at the time of the first peripheral blood mononuclear cell (PBMC) sample included in the IPDA analysis
Summary
The latent HIV-1 reservoir is established early in the course of infection and persists despite suppressive antiretroviral therapy (ART) [1,2,3,4]. In addition to accurately and precisely quantifying the reservoir, it is crucial to understand how its size changes over time in individuals on prolonged suppressive ART. Quantitative viral outgrowth assays (QVOA) measure reactivated virus capable of infecting cells in culture. These assays directly measure the replication-competent population, but their scalability is limited [7]. They are time and labor intensive, with a slow turnaround time to detect outgrowth. The relative stabilities of the intact and defective HIV genomes over time during effective antiretroviral therapy (ART) have not been fully characterized
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