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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

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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 3

Lymphoid IL-10+ cells reside in close spatial proximity to cells harboring SIV-DNA.

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Lymphoid IL-10+ cells reside in close spatial proximity to cells harbori...
(A) IHC was performed for IL-10 in the lymphoid BCF and T cell zone (TCZ) before SIV infection, during chronic SIV infection, or following ART initiated during chronic infection (Supplemental Table 4). Representative IHC shown is rhesus macaque ZI26 at pre-infection, 18 weeks p.i., and 30 weeks p.i. following 12 weeks on ART (3 of 56 unique). Scale bars: 100 μm. (B and C) Percentage of IL-10+ cells by area was determined within the BCF (pink; uninfected, n = 25; chronic, n = 9; ART, n = 14) (B) and TCZ (blue; uninfected, n = 23; chronic, n = 10; ART, n = 12) (C), analyzed by unmatched 1-way ANOVA with Tukey’s correction. (D) DNAscope in situ hybridization for cell-associated viral DNA (vDNA; red) was performed in combination with immunofluorescence imaging to visualize cells costaining with IL-10 (cyan) and p-STAT3 (green) in the LN BCF and non-BCF (i.e., TCZ and medullary cords; RGv10 at 8 months of ART; 1 of 17 unique). Scale bars: 500, 100, 50 μm. Cell numbers were determined with DAPI nuclear stain (gray). The spatial proximity map shows the location of vDNA+ (red) and IL-10+ (yellow) cells as detected and assigned by HALO software (Indica Labs v3.0.311.405) with the nearest neighbor indicated by the proximity line in gray. (E and F) The frequency of p-STAT3+ (chronic, n = 9; ART, n = 8) (E) and vDNA+ (chronic, n = 9; ART, n = 7) (F) cells was calculated based on their spatial proximity to the nearest IL-10+ cell in the BCF and non-BCF during chronic infection and with ART of variable duration (Supplemental Table 4). (B, C, E, and F) Gray shading represents ART, and individual RMs are represented as open (chronic) or filled (ART) circles color-coded per anatomical localization (pink, BCF; blue, non-BCF) with averaged data presented as mean ± SEM (black) that were analyzed with a 1-way (E) or 2-way (F) mixed-effects model with Tukey’s correction.

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