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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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 4

IL-10 predicts the frequency and SIV-DNA content of LN CD4+ Tfh cells during ART.

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IL-10 predicts the frequency and SIV-DNA content of LN CD4+ Tfh cells du...
(A–D) Levels of plasma IL-10 (pg/mL; n = 15; 0.2 pg/mL limit of detection) were measured by an ultrasensitive sandwich immunoassay in chronic infection (d58 p.i.) and were correlated against the following parameters after 7 months of ART (d259 p.i.): cell-associated SIV-DNA content (log10 copies per 106 cells) by RT-qPCR in PBMC CD4+ T cells (n = 15) (A) and rectal biopsy (RB) mononuclear cells (n = 14) (B); frequency of LN Tfh cells (CXCR5+PD-1hi) among CD4+ T cells by flow cytometry (n = 15) (C); and, in a subset of RMs (n = 4), the infectious units per million total CD4+ cells in LNs by QVOA (D). Data from individual RMs are represented as black circles and are overlaid with a simple linear regression (solid blue line) with a 95% confidence interval (blue fill). Correlations were performed by 2-sided Pearson’s correlation coefficient. (E) In PBMCs from chronic infection, transcriptomic signatures of cytokine signaling, survival, and cell cycling were measured by RNA-Seq and correlated against cell-associated SIV-DNA content in LN CD4+ Tfh cells during ART (n = 13). Normalized enrichment scores (NES) are represented by a bidirectional color-coded heatmap. Point size corresponds to the log10-transformed P value with a threshold for highly significant values (P < 0.0001), and significant adjusted P values (P < 0.25) are indicated by a black border (legend at right) as calculated by GSEA.