Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy
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
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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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 2

Plasma IL-10 during chronic infection correlates with lymphoid SIV-DNA content.

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Plasma IL-10 during chronic infection correlates with lymphoid SIV-DNA c...
(A–D) The concentration of plasma IL-10 (pg/mL; 0.2 pg/mL limit of detection) was measured by an ultrasensitive sandwich immunoassay during chronic infection (d58 p.i.) and was correlated against the plasma viral load (log10 SIV-RNA copies/mL; n = 15) (A) and the cell-associated SIV-DNA content (log10 copies per 106 cells) by RT-qPCR in PBMC CD4+ T cells (n = 15) (B), rectal biopsy (RB) mononuclear cells (n = 14) (C), and lymph node (LN) CD4+ T cells (n = 14) (D). (E) LN mononuclear cells underwent FACS for memory CD4+ T cell subsets as follows: central memory (Tcm: PD-1dimCD200–CD95+CCR7+), effector memory (Tem: PD-1dimCD200–CD95+CCR7–), T follicular helper (Tfh; CD200+PD-1hi), and naive (Tn: PD-1dimCD200–CD95–CCR7+). RLm12 at d58 p.i. is shown as a representative sorting strategy pre-gated on singlet lymphocytes (1 of 14 unique sorts with 20,000 pre-sort events). (F–I) Plasma IL-10 (pg/mL) during chronic infection was correlated against the cell-associated SIV-DNA content (log10 copies per 106 cells) in LN CD4+ Tcm (F), LN CD4+ Tem (G), and LN CD4+ Tfh cells (H) (n = 14 each); and the percentage of proliferating (Ki-67+) LN CD4+ Tfh cells by flow cytometry (n = 15) (I). (A–D and F–I) Data from individual macaques are represented as black circles and are overlaid with a simple linear regression (solid blue line) with a 95% confidence interval (blue fill). All correlations were performed using a 2-sided Pearson’s correlation coefficient.