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 Article has an altmetric score of 20

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

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 3

Characterization of defective and infectious proviruses from antigen-responding CD4+ T cell clones.

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Characterization of defective and infectious proviruses from antigen-res...
(A) Genome sequences and integration sites (IS) recovered from proviruses in antigen-responding clones obtained from each participant. Each horizontal bar represents 1 provirus found in CMV- or Gag-responding cells (indicated by teal and purple boxes, respectively). Sequence features are color coded (see legend). The intact provirus from participant P3 is highlighted in black. Captured host-proviral junctions are depicted as squares flanking the horizontal bars, and the gene symbols listed on the right show the gene 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. Proviruses with asymmetrical aberrant integration are marked with black and red squares. (B) Integration sites in BACH2 and STAT5B found in CMV- and Gag-responding clones (teal and purple, respectively) compared with those previously reported in individuals on ART (black). Arrowhead direction represents proviral orientation relative to host gene transcription. The small gray arrows show host gene transcriptional orientation, and the large gray arrows show the translation start site. (C) Summary of the proviral sequences in A. (D) Frequency of infected cells carrying inducible replication-competent proviruses from 5 participants. Horizontal bars show the median and interquartile values. Statistical significance was determined using a 1-way ANOVA. (E) NJ tree including u5-gag sequences from p24-positive qVOA wells, gDNA SGS, and provirus P3.c.FBXO22, sampled according to the inset legend. The highlighter plot shows mismatches from the top sequences in the tree.