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

Simonetti, F. R.; Zhang, H.; Soroosh, G. P.; Duan, J.; Rhodehouse, K.; Hill, A. L.; Beg, S. A.; McCormick, K.; Raymond, H.; Nobles, C. L.; Everett, J.; Kwon, K. J.; White, J. A.; Lai, J.; Margolick, J. B.; Hoh, R.; Deeks, S. G.; Bushman, F. D.; Siliciano, J. D.; Siliciano, R. F.

doi:10.1101/2020.12.01.402651

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bioRxiv · 10.1101/2020.12.01.402651

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 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, full proviral sequence, integration site, and T cell receptor {beta}-chain (TCR{beta}) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated Cytomegalovirus (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. TCR{beta} repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCR{beta}-integration site analysis showed that infection could occur early or late in the course of a clones 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.

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Simonetti, F. R., Zhang, H., Soroosh, G. P., Duan, J., Rhodehouse, K., Hill, A. L., Beg, S. A., McCormick, K., Raymond, H., Nobles, C. L., Everett, J., Kwon, K. J., White, J. A., Lai, J., Margolick, J. B., Hoh, R., Deeks, S. G., Bushman, F. D., Siliciano, J. D., Siliciano, R. F.. 2020-12-01. Antigen-driven clonal selection shapes the persistence of HIV-1 infected CD4+ T cells in vivo. https://doi.org/10.1101/2020.12.01.402651

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