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Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption.

Preprint on Research Square on 14 August 2023 by Sekaly, R. P., Ribeiro, S. P., et al.

HIV persistence during antiretroviral therapy (ART) is associated with heightened plasma IL-10 levels and the expression of the co-inhibitory receptor PD-1. We hypothesized that IL-10 and PD-1 blockade would synergize to boost immune function leading to control of viral rebound post-analytical treatment interruption (ATI). Twenty-eight ART-treated, SIVmac239-infected rhesus macaques (RMs) were treated with anti-IL-10 alone, anti-IL-10 in combination with anti-PD-1 (« combo »), or vehicle. ART was interrupted 12 weeks after the first dose of immunotherapy, which was continued for 14 weeks post-ATI. Durable control of viral rebound (<103 SIV RNA copies per mL plasma) was observed in 8 of 9 (88.9%) combo-treated RMs for more than the 24 weeks of follow up post-ATI. The induction of an inflammatory cytokine environment, proliferation of effector CD8+ T cells in lymph nodes, and reduced expression of BCL-2 in CD4+ T cells in blood and lymph nodes pre-ATI were strong predictors of control of viral rebound. Twenty-four weeks post-ATI, control of viral replication was associated with a rapid expansion of SIV-specific CD4+ and CD8+ T cells in blood and lymph nodes upon in vitro stimulation, followed by the contraction of this memory T cell pool and their differentiation to cells expressing TCF-1, the hallmark transcription factor that regulates stemness. These results provide a mechanistic framework to understand the immunological events that lead to the control of viral rebound post-ATI and map a path to guide the development of a functional cure of chronic HIV/SIV infection.

  • Homo sapiens (Human)
  • Immunology and Microbiology
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