TY - JOUR
T1 - Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy
AU - Harper, Justin
AU - Ribeiro, Susan P.
AU - Chan, Chi Ngai
AU - Aid, Malika
AU - Deleage, Claire
AU - Micci, Luca
AU - Pino, Maria
AU - Cervasi, Barbara
AU - Raghunathan, Gopalan
AU - Rimmer, Eric
AU - Ayanoglu, Gulesi
AU - Wu, Guoxin
AU - Shenvi, Neeta
AU - Barnard, Richard J.O.
AU - Del Prete, Gregory Q.
AU - Busman-Saha, Kathleen
AU - Silvestri, Guido
AU - Kulpa, Deanna A.
AU - Bosinger, Steven E.
AU - Easley, Kirk A.
AU - Howell, Bonnie J.
AU - Gorman, Dan
AU - Hazuda, Daria J.
AU - Estes, Jacob D.
AU - Sekaly, Rafick Pierre
AU - Paiardini, Mirko
N1 - Publisher Copyright:
© 2022, Harper et al.
PY - 2022/4/15
Y1 - 2022/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128489267&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128489267&partnerID=8YFLogxK
U2 - 10.1172/JCI155251
DO - 10.1172/JCI155251
M3 - Article
C2 - 35230978
AN - SCOPUS:85128489267
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
M1 - e155251
ER -