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

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.