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

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 4

Antigen-responding cells show higher clonality and evidence of convergent selection.

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Antigen-responding cells show higher clonality and evidence of convergen...
(A) TCR diversity, estimated by the Chao index (93), was lower in antigen-responding cells. Gray circles represent memory cells nonresponsive to either CMV or Gag stimulation (teal and purple borders, respectively). (B) Gini coefficients based on TCRs from CMV-responding cells showed the highest clonality. (C) Correlation of Gini coefficients based on TCR and proviral populations. Spearman’s r value and linear correlation with 95% CIs are shown. (D) log10 abundance of productive TCRs from CMV-responding cells from participant P1 collected at month 6 and month 9 of the study. (E) VDJ sequences from the 10 most abundant clonotypes encoding CASRGSTEAFF. (F) Summed abundance of all degenerate and expanded CDR3β sequences. (G) Frequency of TCR clusters normalized by CDR3β input. Clusters were filtered on the basis of CDR3β of 2 or greater and a Fisher’s exact test P < 0.0001. (H) TCR clusters are plotted on the basis of the number of total CDR3β and Vβ gene scores. Lower scores indicate more homogeneous Vβ. Circle size is scaled to the total sum of TCR templates in each group, indicating clonal expansion of cells within the cluster. (I) Representative TCR clusters involving more than 1 participant, displayed as networks and CDR3β sequence logos. Nodes represent each CDR3β sequence, with circle colors based on participant and circle size representing clonal expansion. Edge colors highlight antigen stimulation (teal for CMV and purple for Gag). CDR3β logos display amino acid representation at each position. The core motif shared by the convergent cluster is colored. The table shows cluster characteristics and shared HLA alleles (see Supplemental Table 4 for additional details). Exclamation marks indicate enrichment of the participants’ HLA allele contributing to the cluster. Horizontal bars show the median and interquartile values. Statistical significance was determined by 1-way ANOVA.