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Antigen-driven clonal selection shapes the persistence of HIV-1–infected CD4+ T cells in vivo
Francesco R. Simonetti, … , Janet D. Siliciano, Robert F. Siliciano
Francesco R. Simonetti, … , Janet D. Siliciano, Robert F. Siliciano
Published December 10, 2020
Citation Information: J Clin Invest. 2021;131(3):e145254. https://doi.org/10.1172/JCI145254.
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Research Article AIDS/HIV Immunology

Antigen-driven clonal selection shapes the persistence of HIV-1–infected CD4+ T cells in vivo

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Abstract

Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.

Authors

Francesco R. Simonetti, Hao Zhang, Garshasb P. Soroosh, Jiayi Duan, Kyle Rhodehouse, Alison L. Hill, Subul A. Beg, Kevin McCormick, Hayley E. Raymond, Christopher L. Nobles, John K. Everett, Kyungyoon J. Kwon, Jennifer A. White, Jun Lai, Joseph B. Margolick, Rebecca Hoh, Steven G. Deeks, Frederic D. Bushman, Janet D. Siliciano, Robert F. Siliciano

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Figure 6

Total body clone sizes and contribution of CD4+ T cell subsets.

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Total body clone sizes and contribution of CD4+ T cell subsets.
(A) Prov...
(A) Proviral and VDJ frequencies were used to back-calculate total body clone sizes. Clones with integration sites in genes previously linked to the persistence of infected cells are highlighted in red. Venn diagrams show the fraction of a clonotype (orange) carrying its cognate provirus (blue). (B) Two scenarios of infection-expansion dynamics of antigen-driven clonal selection. The left panel shows infection of a clone already expanded in response to antigen, whereas the right panel shows selection occurring after an early infection event. (C) Contribution of CD4+ T cell memory subsets to clones based on provirus and VDJ measurements. Memory subsets are defined as shown in Supplemental Figure 10. Horizontal bars show the relative contribution of memory subsets for each clone. Gene symbols show the genes containing or closest to (indicated by an asterisk) the integration site. Genes previously linked to the persistence of HIV-1–infected cells are highlighted in red.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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