BACKGROUND. The relative stabilities of the intact and defective HIV genomes over time during effective antiretroviral therapy (ART) have not been fully characterized. METHODS. We used the intact proviral DNA assay (IPDA) to estimate the rate of change of intact and defective proviruses in HIV-infected adults on ART over several years. We used linear spline models with a knot at seven years; these included a random intercept and slope up to the knot. We also estimated the influence of covariates on starting levels and rates of change. RESULTS. We studied 81 individuals for a median of 7.3 (IQR 5.9–9.6) years. In a model allowing for a change in the rate of decline, we found evidence for a more rapid rate of decline in intact genomes from initial suppression through seven years (15.7% per year decline; CI –22.8%, –8.0%) followed by a slower rate of decline after seven years (3.6% per year; CI –8.1%, +1.1%). The estimated half-life of the reservoir was 4.0 years (CI 2.7–8.3) until year seven and 18.7 years (CI 8.2–infinite) thereafter. There was substantial variability between individuals in the rate of decline until year seven. Intact provirus declined at a faster rate than defective provirus (P < 0.001). Individuals with higher CD4+ T cell nadir values had a faster rate of decline in intact provirus. CONCLUSIONS. These findings provide evidence that the 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. FUNDING. This work was supported the Delaney AIDS Research Enterprise (DARE; AI096109, A127966). The SCOPE cohort receives additional support from the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763), the CFAR Network of Integrated Systems (R24 AI067039) and the amfAR Institute for HIV Cure Research (amfAR 109301). Additional support was provided by the I4C and Beat-HIV Collaboratories, the Howard Hughes Medical Institute, Gilead, and the Bill and Melinda Gates Foundation.
Michael J. Peluso, Peter Bacchetti, Kristen D. Ritter, Subul A. Beg, Jun Lai, Jeffrey N. Martin, Peter W. Hunt, Timothy J. Henrich, Janet D. Siliciano, Robert F. Siliciano, Gregory M. Laird, Steven G. Deeks
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