Figure 7.

HCV and induction of the innate immune response. HCV activates the innate immune response through the endosomal TLR3 via dsRNA structures (derived from apoptotic of necrotic infected cells) present in the inoculum and through the intracytosolic RNA helicase RIG-I after entry of the viral RNA into the cytosol. Activation through TLR7 is not represented here. Binding of RIG-I to viral dsRNA structures triggers a change in its conformation and its dimerization/multimerization. RIG-I becomes ubiquitined (grey circles) by the E3 ligase TRIM25, which allows its interaction with the mitochondria-bound protein MAVS [157] (MAVS is also known as Cardif [158], VISA [159] and IPS-1 [160]). MAVS recruits different adapters such as members of the TRAF family and the downstream kinases IKKβ, TBK1 and IKKε which activate the transcription factors NF-κB and IRF3, respectively. In addition, the MAVS pathway can also lead to activation of AP-1 (ATF-2/C-jun) (not represented). Upon binding to dsRNA, TLR3 recruits the intracytosolic adapter TRIF, which itself recruits members of the TRAF family, the adapter RIP-1 (Receptor-Interacting Protein 1) and the NF-κB- and IRF3‑activating kinases. In addition, the TLR3 pathway triggers induction of AP-1 through PI3K/Akt. Combination of the three transcription factors is necessary for efficient induction of IFNβ, while IRF3 alone is sufficient for induction of a series of genes, referred to as VISGs (Virus Stress Inducible Genes), which will be later on responsive to IFN. NF-κB stimulates the transcription of pro-inflammatory genes. Box: The HCV NS3/4A protease has the capacity to abrogate induction of the innate immune response through the cleavage of TRIF, close to its Toll-like/IL-1 Receptor (TIR)-domain and of MAVS, close to its transmembrane domain. The sequence of the cleavage sites is shown. CARD stands for Caspase Recognition Domain.