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 5

IL-10 neutralization inhibits memory CD4+ T cell homeostasis in vivo.

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IL-10 neutralization inhibits memory CD4+ T cell homeostasis in vivo. (A...
(A) Six RMs were infected i.v. with SIVmac239 and, at d35 p.i., began daily ART. All RMs received an anti–IL-10 mAb at d211 p.i. (10 mg/kg) and at d238 p.i. (20 mg/kg) followed by necropsy (NX) at d263 p.i. Tissue collections, including blood, LN biopsy, and rectal biopsy, are indicated below. (B) Longitudinal plasma viral loads (SIV-RNA copies/mL) were determined by RT-qPCR with 6 replicate reactions (15-copies/mL limit of detection indicated by horizontal dashed line; n = 6). (C and D) During the intervention, the plasma concentration of the anti–IL-10 mAb (μg/mL; 2 μg/mL limit of detection indicated by horizontal dashed line; n = 6) (C) and the levels of plasma IL-10 (pg/mL; 10 pg/mL limit of detection indicated by horizontal dashed line; n = 6) (D) were measured by electrochemiluminescent sandwich immunoassay on a MesoScale platform. Plasma was drawn immediately before and 5 minutes after infusion of the anti–IL-10 mAb (d211 and d238 p.i.). (B–D) Individual RMs are given by color-coded, solid lines, and no statistics were performed. (B–D) 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. (E) RNA-Seq was performed on PBMCs (n = 5) from the on-ART, treatment baselines (gray; d167 and d209 p.i.), and following administration of the anti–IL-10 mAb (purple; d229 and d263; as color-coded above). On individual RMs (as indicated above), sample-level enrichment analysis (SLEA) was performed to measure the expression of transcriptomic pathways associated with cell survival and differentiation (as indicated at left), and the enrichment score is given as a bidirectional heatmap (P < 0.05 for all shown measures).