Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy

• Type of Material: Article
• Authors: Justin Harper, Emory University; Susan P. Ribeiro, Case Western Reserve University; Chi Ngai Chan, Oregon Health and Science University; Malika Aid, Beth Israel Deaconess Medical Center; Claire Deleage, National Cancer Institute; Luca Micci, Emory University; Maria Pino, Emory University; Barbara Cervasi, Emory University; Gopalan Raghunathan, Merck & Co Inc; Eric Rimmer, Merck & Co Inc; Gulesi Ayanoglu, Merck & Co Inc; Guoxin Wu, Merck & Co Inc; Neeta Shenvi, Emory University; Richard J. O. Barnard, Merck & Co Inc; Gregory Q. Del Prete, National Cancer Institute; Kathleen Busman-Sahay, Oregon Health and Science University; Guido Silvestri, Emory University; Deanna Kulpa, Emory University; Steven Bosinger, Emory University; Kirk Easley, Emory University; Bonnie J. Howell, Merck & Co Inc; Dan Gorman, Merck & Co Inc; Daria J. Hazuda, Merck & Co Inc; Jacob D. Estes, Oregon Health and Science University; Rafick-Pierre Sekaly, Emory University; Mirko Paiardini, Emory University
• Language: English
• Date: 2022-04-15
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Harper et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI155251
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 132
• Issue: 8
• Grant/Funding Information: Funding for this work was provided via the following awards: NIH/NIAID grant R01AI116379 to M Paiardini; NIH/NIAID grants R21AI122380 and R37AI141258 to RPS; NIH/NHLBI/NIDDK/NINDS/NIDA/NIAID grant UM1AI164562 to M Paiardini, DAK, and GS; NIH/OD grants P51OD011132 and U42OD011023 to the Yerkes National Primate Research Center; NIH/NCRR grant R24RR016988 to the Emory Vaccine Center for AIDS Research; NIH/OD grants P51OD011092 and 1S10OD025002-01 to the Oregon National Primate Research Center; and NIH/NCI grants 75N91019D00024 and HHSN261200800001E to Leidos Biomedical Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
• Keywords: Research & Experimental Medicine; CYTOKINE PRODUCTION; RESPONSES; FOLLICULAR-HELPER-CELLS; Science & Technology; Medicine, Research & Experimental; Life Sciences & Biomedicine; C-MAF; IL-10; ANTIGEN-PRESENTING CELL; CD4 T-CELL; HIV-INFECTION; IFN-GAMMA; TRANSCRIPTION
• Research Categories: Biology, Virology; Biology, Cell

Abstract

Interleukin-10 (IL-10) is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper (Tfh) cell differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph nodes (LNs) were induced by infection and not normalized with antiretroviral therapy (ART). During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including Tfh cells, and predicted the frequency of CD4+ Tfh cells and their cell-associated SIV-DNA content during ART, respectively. In ART-treated rhesus macaques, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and, by extension, LN memory CD4+ T cells, including Tfh cells and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.