Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy
Justin Harper, … , Rafick-Pierre Sekaly, Mirko Paiardini
Justin Harper, … , Rafick-Pierre Sekaly, Mirko Paiardini
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(8):e155251. https://doi.org/10.1172/JCI155251.
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Research Article AIDS/HIV Immunology

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

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.

Authors

Justin Harper, Susan P. Ribeiro, Chi Ngai Chan, Malika Aid, Claire Deleage, Luca Micci, Maria Pino, Barbara Cervasi, Gopalan Raghunathan, Eric Rimmer, Gulesi Ayanoglu, Guoxin Wu, Neeta Shenvi, Richard J.O. Barnard, Gregory Q. Del Prete, Kathleen Busman-Sahay, Guido Silvestri, Deanna A. Kulpa, Steven E. Bosinger, Kirk A. Easley, Bonnie J. Howell, Dan Gorman, Daria J. Hazuda, Jacob D. Estes, Rafick-Pierre Sekaly, Mirko Paiardini

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Figure 6

IL-10 neutralization impairs the survival of LN memory and CD4+ Tfh cells.

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IL-10 neutralization impairs the survival of LN memory and CD4+ Tfh cell...
(A and B) Flow cytometry was performed on fresh LN mononuclear cells (n = 6) in which the frequencies of total memory (CD95+) (A) and Tfh (CXCR5+PD-1hi) (B) cells among CD4+ T cells were quantified. (C) For the Tfh cell quantification, flow cytometry stains of CXCR5 against PD-1 inside the parental CD4+ T cell population are shown for all animals (n = 6, 18 of 30 unique; indicated at right) at the indicated time points (above). Gates and the percentage of parent are given in red. Time points analyzed include during chronic infection (d35 p.i.); the on-ART, pretreatment baselines (d167 and d209 p.i.); and at d18 (d229 p.i.) and d25 (d263 p.i.) after administration of 10 or 20 mg/kg of anti–IL-10 mAb, respectively. (D–G) Flow cytometry was also used to measure the frequency of Tregs (CD25+CD127–FoxP3+) among memory CD4+ T cells in LNs (D) and PBMCs (E); ICR coexpression, CTLA-4+PD-1hi, in memory CD4+ T cells (F); and activation (HLA-DR+CD38+) in CD4+ Tfh cells (n = 6 each) (G). (A, B, and D–G) Data from individual macaques are represented by tethered, open black circles with averaged data presented as mean (blue line) ± SEM (blue filled area) and were analyzed by 2-sided, 1-way ANOVA with matching using a Dunnett’s correction for multiple comparisons relative to the intervention baseline (d209 p.i.). ART is represented as a gray-shaded background, whereas anti–IL-10 mAb infusions are given by vertical dashed lines (purple) with the intervention phase amid ongoing ART represented as a purple-shaded background.