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 2

HIV-1–infected, CMV-responding cells are enriched in proviral populations generated by clonal expansion.

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HIV-1–infected, CMV-responding cells are enriched in proviral population...
(A) Representative NJ tree of 186 independent HIV-1 u5-gag DNA SGSs from participant P2, rooted to the HIV-1 subtype C consensus. Sequences from different sorted populations are color coded (see legend). A branch distance of 1 nucleotide is shown on the tree scale. (B) Frequencies of identical proviral sequences within sorted populations for all 10 participants. (C) NJ trees of HIV-1 sequences recovered from CMV-responding CD4+ T cells from 4 participants. Identical sequences are collapsed onto the same branch, and trees are rooted to the HIV-1 subtype B consensus sequence. Dashed branches indicate hypermutated proviruses. Symbols indicate the method and time point used to generate the sequences. Large CMV-specific clones are colored as in D, and the gene containing or closest to the integration site is indicated (see Supplemental Table 3 for detailed integration site data). (D) Dot plot showing increased frequencies of probable clones identified in CMV-responding cells compared with cells responding to anti-CD3/anti-CD28 stimulation or CMV-nonresponding memory cells. Only clones confirmed by integration site or potential clones composed of at least 4 sequences were included. Probable clones are color-coded across stimulation conditions and as in C and Supplemental Figure 4. (E) Dot plot showing higher clonality of proviral populations from CMV-responding cells measured with the Gini coefficient. Horizontal bars show the median and interquartile range. Statistical significance was determined by 1-way ANOVA. CMV-nr, CMV-nonresponding; CMV-re, CMV-responding; Gag-re, Gag-responding; Memory nr, CMV-nonresponding memory cells. Gene symbols next to the tree branches 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