The Journal of Clinical Investigation (Apr 2022)

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

Journal volume & issue
Vol. 132, no. 8

Abstract

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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.

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