HIV-1 evades immune detection by the cGAS-STING cytosolic DNA sensing pathway during acute infection. STING is a critical mediator of type I interferon production, and STING agonists such as cyclic GMP-AMP (cGAMP) and other cyclic dinucleotides elicit potent immune and anti-tumor response. Here, we show that administration of cGAMP, delivered by an ultra-pH sensitive nanoparticle (PC7A), in human peripheral blood mononuclear cells (PBMCs) induces potent and long-acting antiretroviral response against several laboratory-adapted and clinical HIV-1 isolates. cGAMP-PC7A NP requires endocytosis for intracellular delivery and immune signaling activation, and cGAMP-PC7A NP-induced protection is mediated through type I interferon signaling and requires monocytes in PBMCs. cGAMP-PC7A NP also inhibited HIV-1 replication in HIV-positive patient PBMCs after ex vivo reactivation. As pattern recognition receptor agonists continue to show more clinical benefits than the traditional interferon therapy, our data present important evidence for potentially developing cGAMP or other STING agonists as a new class of immune-stimulating long-acting antiretroviral agents.
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