HIV-1 latent reservoir size and diversity are stable following brief treatment interruption
D. Brenda Salantes, … , Pablo Tebas, Katharine J. Bar
D. Brenda Salantes, … , Pablo Tebas, Katharine J. Bar
Published June 18, 2018
Citation Information: J Clin Invest. 2018;128(7):3102-3115. https://doi.org/10.1172/JCI120194.
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Clinical Medicine AIDS/HIV Clinical trials

HIV-1 latent reservoir size and diversity are stable following brief treatment interruption

Abstract

BACKGROUND. The effect of a brief analytical treatment interruption (ATI) on the HIV-1 latent reservoir of individuals who initiate antiretroviral therapy (ART) during chronic infection is unknown. METHODS. We evaluated the impact of transient viremia on the latent reservoir in participants who underwent an ATI and at least 6 months of subsequent viral suppression in a clinical trial testing the effect of passive infusion of the broadly neutralizing Ab VRC01 during ATI. RESULTS. Measures of total HIV-1 DNA, cell-associated RNA, and infectious units per million cells (IUPM) (measured by quantitative viral outgrowth assay [QVOA]) were not statistically different before or after ATI. Phylogenetic analyses of HIV-1 env sequences from QVOA and proviral DNA demonstrated little change in the composition of the virus populations comprising the pre- and post-ATI reservoir. Expanded clones were common in both QVOA and proviral DNA sequences. The frequency of clonal populations differed significantly between QVOA viruses, proviral DNA sequences, and the viruses that reactivated in vivo. CONCLUSIONS. The results indicate that transient viremia from ATI does not substantially alter measures of the latent reservoir, that clonal expansion is prevalent within the latent reservoir, and that characterization of latent viruses that can reactivate in vivo remains challenging. TRIAL REGISTRATION. ClinicalTrials.gov NCT02463227 FUNDING. Funding was provided by the NIH.

Authors

D. Brenda Salantes, Yu Zheng, Felicity Mampe, Tuhina Srivastava, Subul Beg, Jun Lai, Jonathan Z. Li, Randall L. Tressler, Richard A. Koup, James Hoxie, Mohamed Abdel-Mohsen, Scott Sherrill-Mix, Kevin McCormick, E. Turner Overton, Frederic D. Bushman, Gerald H. Learn, Robert F. Siliciano, Janet M. Siliciano, Pablo Tebas, Katharine J. Bar

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Figure 3

ML phylogenetic trees of SGS-derived gp160 env sequences from pre-ART plasma, rebound plasma, and replication-competent latent viruses for participants A01, A02, and A05–A07.

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ML phylogenetic trees of SGS-derived gp160 env sequences from pre-ART pl...
Env sequences from pre-ART plasma are shown as black circles, sequences from rebound plasma from the first and second weeks of detectable viremia after ATI are shown as red and orange triangles, respectively, and sequences from virus supernatant from individual pre- and post-ATI p24+ QVOA culture supernatants are shown as solid blue or open blue squares. Genetic distance is shown by the scale bar, indicating 5 nucleotides (or ~0.2% difference). Bootstrap values above 70 are indicated by asterisks. Envs tested for neutralization sensitivity (Neut tested) in participants A01, A02, and A06 are indicated with an inverted v (^). Populations of identical QVOA sequences are seen in participants A01, A02, and A06, including a single dominant clone in participant A01 representing 95% of all QVOA sequences. Rebound sequences are generally distinct from QVOA sequences, except in participant A06, in which limited genetic diversity challenged distinction and in A07, in which the single QVOA sequence aligned with a rebound lineage.