Innate immune defenses are essential for restricting virus replication and spread, and for programming the adaptive immune response for protection against infection. Our studies have revealed key features of innate immunity, starting with nonself discrimination for identification of virus infection, to innate immune effector genes and responses that serve to restrict viral replication and spread. Studies of hepatitis C virus (HCV), a heptotropic RNA virus, have identified RIG-I-like receptors (RLR) signaling of interferon regulatory factor (IRF)3 activation as a critical event initiating the innate immune response to infection from within the host cell. This process propagates through induction of innate immune effectors genes, including type 1 and 3 interferons and interferon stimulated genes (ISGs). ISG products include antiviral factors that restrict virus replication, and proinflammatory cytokines and chemokines that facilitate innate immune cell activation and lymphocyte response toward the infected liver. HCV disrupts these process through the actions of the viral NS3/4A protease that cleaves MAVS, a key adaptor protein in the RLR pathway, resulting in loss of IRF3 activation and target gene expression, thus supporting viral persistence. Comparison of innate immune signaling outcomes within cells infected with HCV or HIV defines viral regulation of IRF3, and suppression of ISG products, as shared feature of chronic virus infection. Our studies reveal specific nodes of the innate immune response that are subject to viral and host control, and whose actions impart control over the progression of acute to chronic infection transition. Targeting innate immune actions of the host should be formally considered in therapeutic strategies to interrupt persistence for clearance of chronic virus infection.
CROI Conference
