The role of CD101-expressing CD4 T cells in HIV/SIV pathogenesis and persistence

• Type of Material: Article
• Authors: Zachary Strongin, Emory University; Timothy N Hoang, Emory University; Gregory K Tharp, Emory University; Andrew R Rahmberg, National Institute of Allergy and Infectious Diseases (NIAID); Justin L Harper, Emory University; Kevin Nguyen, Emory University; Lavinia Franchitti, Emory University; Barbara Cervasi, Emory University; Max Lee, National Institutes of Health (NIH); Zhan Zhang, Emory University; Eli A Boritz, National Institutes of Health (NIH); Guido Silvestri, Emory University; Vincent Marconi, Emory University; Steven Bosinger, Emory University; Jason M Brenchley, National Institute of Allergy and Infectious Diseases (NIAID); Deanna Kulpa, Emory University; Mirko Paiardini, Emory University
• Language: English
• Date: 2022-07-01
• Publisher: PLoS
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1010723
• Title of Journal or Parent Work: PLoS Pathogens
• Volume: 18
• Issue: 7
• Start Page: e1010723
• End Page: e1010723
• Grant/Funding Information: This work was supported by the NIAID, NIH under award numbers: R01AI116379 and R21/R33AI116171 (M.P.), and R37AI141258.; This work was also supported by UM1AI164562 (G.S.; D.A.K.; M.P.), co-funded by NIH/NHLBI/NIDDK/NINDS/NIDA/NIAID. Additional support was provided by the NIH OD, ORIP, P51 OD011132 and U42 OD011023, and Division of Intramural Research, NIAID, P30AI050409. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: HIV Infections; CD4-Positive T-Lymphocytes; Simian Acquired Immunodeficiency Syndrome; Macaca mulatta; Animals; Humans; Simian Immunodeficiency Virus

Abstract

Despite the advent of effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) continues to pose major challenges, with extensive pathogenesis during acute and chronic infection prior to ART initiation and continued persistence in a reservoir of infected CD4 T cells during long-term ART. CD101 has recently been characterized to play an important role in CD4 Treg potency. Using the simian immunodeficiency virus (SIV) model of HIV infection in rhesus macaques, we characterized the role and kinetics of CD101+ CD4 T cells in longitudinal SIV infection. Phenotypic analyses and single-cell RNAseq profiling revealed that CD101 marked CD4 Tregs with high immunosuppressive potential, distinct from CD101Tregs, and these cells also were ideal target cells for HIV/SIV infection, with higher expression of CCR5 and α4β7 in the gut mucosa. Notably, during acute SIV infection, CD101+ CD4 T cells were preferentially depleted across all CD4 subsets when compared with their CD101counterpart, with a pronounced reduction within the Treg compartment, as well as significant depletion in mucosal tissue. Depletion of CD101+ CD4 was associated with increased viral burden in plasma and gut and elevated levels of inflammatory cytokines. While restored during long-term ART, the reconstituted CD101+ CD4 T cells display a phenotypic profile with high expression of inhibitory receptors (including PD-1 and CTLA-4), immunsuppressive cytokine production, and high levels of Ki-67, consistent with potential for homeostatic proliferation. Both the depletion of CD101+ cells and phenotypic profile of these cells found in the SIV model were confirmed in people with HIV on ART. Overall, these data suggest an important role for CD101-expressing CD4 T cells at all stages of HIV/SIV infection and a potential rationale for targeting CD101 to limit HIV pathogenesis and persistence, particularly at mucosal sites.