Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection

Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection

“…However, presentation of viral Ag by DCs may prove to be a double-edged sword: to induce HCVspecific immune responses it is necessary for DCs to interact with HCV to deliver Ags and appropriate signals to T cells, leaving the HCV-presenting DCs susceptible to functional alterations by the virus. Proteolytic cleavage of adaptors Toll/IL-1 domain-containing adapter-inducing IFN-b (TRIF) and IFN-b promoter stimulator (IPS)-1 by HCV's NS3/4A serine protease suppresses the activation of innate immunity by well-characterized PRRs, TLR3 and retinoic acid-inducible gene (RIG)-I, respectively (11)(12)(13). Pertinently, HCV RNA density-dependent attenuation of IL-12 and TNF-a production by myeloid DCs (MDCs) after TLR3 and TLR4 stimulation, both TRIF-dependent pathways, was reported to occur in HCV-infected patients versus aviremics (14).…”

Innate immune evasion by hepatitis C virus and West Nile virus

“…These efforts identified IPS-1/Cardif/MAVS/VISA, as an essential adaptor protein of RIG-I signaling [reviewed in reference 29]. Studies of HCV infection demonstrated that IPS-1 was targeted and cleaved by the NS3/4A protease during virus replication [33,36]. We found that NS3/4A targets and cleaves endogenous IPS-1 in vitro and in vivo [33].…”

“…Studies of HCV infection demonstrated that IPS-1 was targeted and cleaved by the NS3/4A protease during virus replication [33,36]. We found that NS3/4A targets and cleaves endogenous IPS-1 in vitro and in vivo [33]. Mechanistically, this cleavage event occurs at cysteine 508 of IPS-1 to release it from its membrane anchor.…”

“…Our in vitro studies of the HCV RNA replicon model and of cells infected with the JFH1 HCV 2A infectious clone demonstrated that HCV imposes a blockade to RIG-I signaling of α/β IFN production [32,33]. Analysis of viral protein function identified the HCV NS3/4A protein complex an antagonist of virusinduced IRF-3 activation [34].…”

“…Protein function studies now demonstrate that NS3/4A targeting of IPS-1 occurs through the protease domain and its minimal NS4A cofactor alone, and does not involve the NS3 helicase domain [35]. Moreover, NS3/4A protease inhibitors can effectively prevent proteolysis of IPS-1 during HCV infection, and treatment of infected cells actually restores the innate immune response to infection even in the presence of NS3/4A [33,35]. Thus, IPS-1 is an essential signal transducer of the RIG-I pathway that is targeted and cleaved by NS3/4A during infection (Fig 2).…”