TY - JOUR
T1 - Antigen-driven clonal selection shapes the persistence of HIV-1-infected CD4+T cells in vivo
AU - Simonetti, Francesco R.
AU - Zhang, Hao
AU - Soroosh, Garshasb P.
AU - Duan, Jiayi
AU - Rhodehouse, Kyle
AU - Hill, Alison L.
AU - Beg, Subul A.
AU - McClurkan, Kevin
AU - Raymond, Hayley E.
AU - Nobles, Christopher L.
AU - Everett, John K.
AU - Kwon, Kyungyoon J.
AU - White, Jennifer A.
AU - Lai, Jun
AU - Margolick, Joseph B.
AU - Hoh, Rebecca
AU - Deeks, Steven G.
AU - Bushman, Frederic D.
AU - Siliciano, Janet D.
AU - Siliciano, Robert F.
N1 - Funding Information:
We thank the participants who volunteered to take part in this study and their families. We thank Guido Massaccesi and Andrea L. Cox for providing PBMCs from donors with known cell-mediated responses to CMV. We thank Srona Sengupta, Annie A. Antar, Janelle Montagne, and H. Benjamin Larman for discussions leading to this work, and Monica Sullivan for the administrative support. This work was supported by the NIH Martin Del-aney, Beat-HIV (UM1 AI126620), and Delaney AIDS Research Enterprise (DARE) (UM1 AI12661) Collaboratories; the Howard Hughes Medical Institute; and the Bill and Melinda Gates Foundation (OPP1115715). This work was also supported by NIH grants DP5OD019851, U19-AI117950, R01AI129661, and R01CA241762; the Penn Center for AIDS Research (P30AI045008); and the Pen-nCHOP Microbiome Program.
Funding Information:
We thank the participants who volunteered to take part in this study and their families. We thank Guido Massaccesi and Andrea L. Cox for providing PBMCs from donors with known cellmediated responses to CMV. We thank Srona Sengupta, Annie A. Antar, Janelle Montagne, and H. Benjamin Larman for discussions leading to this work, and Monica Sullivan for the administrative support. This work was supported by the NIH Martin Delaney, Beat-HIV (UM1 AI126620), and Delaney AIDS Research Enterprise (DARE) (UM1 AI12661) Collaboratories; the Howard Hughes Medical Institute; and the Bill and Melinda Gates Foundation (OPP1115715). This work was also supported by NIH grants DP5OD019851, U19-AI117950, R01AI129661, and R01CA241762; the Penn Center for AIDS Research (P30AI045008); and the PennCHOP Microbiome Program.
Publisher Copyright:
Copyright © 2021, American Society for Clinical Investigation.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100380732&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100380732&partnerID=8YFLogxK
U2 - 10.1172/JCI145254
DO - 10.1172/JCI145254
M3 - Article
C2 - 33301425
AN - SCOPUS:85100380732
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 3
M1 - e145254
ER -