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 1

IL-10 during chronic infection correlates with signatures of T cell exhaustion and survival.

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IL-10 during chronic infection correlates with signatures of T cell exha...
(A) Plasma IL-10 levels (pg/mL; 0.2 pg/mL limit of detection) were assessed by an ultrasensitive sandwich immunoassay at pre-infection (d–20 p.i.), at chronic SIV infection (d58 p.i.), and during suppressive ART (d135 and d259 p.i.; n = 15). Ongoing ART is given by the gray-shaded background, and data from individual RMs are represented by tethered, open black circles with averaged data presented as mean (blue line) ± SEM (blue filled area). Data were analyzed with 2-sided, 1-way ANOVA using Holm-Šidák correction for multiple comparisons between all time points. (B) In PBMCs (n = 15), mRNA transcripts of genes associated with activation, Tfh cell homeostasis, and immune checkpoint receptor (ICR) expression were measured by RNA-Seq (annotated at left). The log2 fold change in abundance over time (i.e., between d–20, d58, and d241 p.i., as indicated below) is indicated by the 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 < 0.05) are indicated by a black border (legend at right). (C) Transcriptomic signatures of exhaustion, survival, and activation were measured by RNA-Seq in PBMCs (n = 15) at chronic infection (as annotated at left) and were correlated against levels of plasma IL-10 (pg/mL) during chronic infection. 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 < 0.001), and significant adjusted P values (P < 0.25) are indicated by a black border (as shown at right). (B and C) Statistical analyses were calculated by gene set enrichment analysis (GSEA).