HIV-1 latent reservoir size and diversity are stable following brief treatment interruption
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
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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Clinical Research and Public Health AIDS/HIV

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 6

ML phylogenetic trees of SGS-derived gp160 env sequences from pre-ART plasma, rebound plasma, replication-competent latent viruses, and genetically intact proviral DNA 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, sequences from virus supernatant from pre- and post-ATI individual p24+ QVOA culture well supernatants are shown as solid blue or open blue squares, and sequences from pre- and post-ATI proviral DNA (pDNA) are shown as solid purple or open purple diamonds. For clearer visualization, identical sequences are aligned horizontally in rows of 5. Genetic distance is shown by the scale bar, indicating 5 nucleotides (or ~0.2% difference) in all trees. Bootstrap values above 70 are indicated by asterisks. Populations of identical proviral DNA sequences are seen in all participants, including a large clonal population in participant A02 comprising 61% of total proviral DNA sequences. In general, the larger clonal populations of proviral DNA sequences show limited or no overlap with the larger QVOA clones.