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 Article has an altmetric score of 6

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 7

IL-10 neutralization reduces SIV-DNA content in LNs independent of SIV-specific T cell responses.

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IL-10 neutralization reduces SIV-DNA content in LNs independent of SIV-s...
(A) DNAscope in situ hybridization for cell-associated vDNA (red, indicated by arrows) was performed in combination with immunofluorescence imaging for a DAPI nuclear stain (gray) and CD20 (green) to define cell numbers and demarcate the BCF (white, dashed outlines), respectively. Representative DNAscope IHC and immunofluorescence images of formalin-fixed, paraffin-embedded LN from RRs15 at d35, d209, and 263 p.i. are shown (3 of 15 unique samples); bottom panels show boxed regions from top panels at higher magnification. Scale bars: 100, 50 μm. (B and C) Using these images, the vDNA content per 106 cells was measured in the LN BCF (B) and TCZ (C) (n = 5 each). 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 Tukey’s correction for multiple comparisons between all factors. (D–K) Cryopreserved, rested PBMCs were stimulated with overlapping SIVmac239 GAG peptide pools, and by flow cytometry the frequency of CD107a+, IFN-γ+, IL-2+, and TNF-α+ cells was measured in memory CD4+ T cells (D–G) and memory CD8+ T cells (H–K), respectively (n = 6 each; RSr15 unavailable at baseline). Reported values have had background expression levels detected in the mock-stimulated condition subtracted. (D–K) Data from individual macaques are represented as color-coded circles with averaged data presented as mean ± SEM (red) and were analyzed by 2-sided, 1-way mixed-effects model using Tukey’s correction for multiple comparisons between all time points. (D–K) 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.