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

被引：114

作者：

Simonetti, Francesco R. ^{[1
]}

Zhang, Hao ^{[2
]}

Soroosh, Garshasb P. ^{[1
]}

Duan, Jiayi ^{[1
]}

Rhodehouse, Kyle ^{[1
]}

Hill, Alison L. ^{[3
]}

Beg, Subul A. ^{[1
]}

McCormick, Kevin ^{[4
]}

Raymond, Hayley E. ^{[4
]}

Nobles, Christopher L. ^{[4
]}

Everett, John K. ^{[4
]}

Kwon, Kyungyoon J. ^{[1
]}

White, Jennifer A. ^{[1
]}

Lai, Jun ^{[1
]}

Margolick, Joseph B. ^{[2
]}

Hoh, Rebecca ^{[5
]}

Deeks, Steven G. ^{[5
]}

Bushman, Frederic D. ^{[4
]}

Siliciano, Janet D. ^{[1
]}

Siliciano, Robert F. ^{[1
,6
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Med, 733 N Broadway, Baltimore, MD 21205 USA

[2] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA

[3] Johns Hopkins Univ, Inst Computat Med, Baltimore, MD USA

[4] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA

[5] UCSF, Div HIV Infect Dis & Global Med, San Francisco, CA USA

[6] Howard Hughes Med Inst, Baltimore, MD USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2021年 / 131卷 / 03期

关键词：

RETROVIRAL INSERTION SITES; HIV-1 LATENT RESERVOIR; ANTIRETROVIRAL THERAPY; PUBLIC DATABASE; REPLICATION; INTEGRATION; CYTOMEGALOVIRUS; PROLIFERATION; RESPONSES; EFFECTOR;

D O I：

10.1172/JCI145254

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 beta-chain (TCR beta) 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. TCRIS repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STATSB, the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCR beta 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.

引用

页数：16

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