also found TLR4 SNPs rs4986791 and rs960312 were associated with increased fibrosis risk.[103] Carriage

of Asp299Gly and Thr399Gly is approximately 8% in Caucasian populations, while SNP rs960312 is important for its high prevalence within Asian populations (up to 25%). It has been shown that protective variants lower the apoptotic threshold of hepatocytes, inhibit TLR4 and NFκB signaling, and are associated with greater spontaneous apoptosis of HSCs.[104] By contrast, Eid et al.[105] found that in the post-transplant HCV setting, TLR2 polymorphism Arg753Gln homozygosity was strongly associated with rapid HCV fibrosis progression but found no association between TLR4 polymorphisms and adverse outcomes. The TLR7 gene is located on the X chromosome, and three SNPs in this gene have been identified with > 5% carriage within Caucasian Y-27632 cell line populations: c.1-120T>G (rs2302267), c.32A>T (rs179008, Gln11Leu), and c.2403C>A (rs5743781, Ala448Val).[106] In chronic HCV infection, c.1-120TVemurafenib mouse to explain reduced hepatic fibrosis, as IL-6 has been shown in various studies to be antifibrotic.[92-94] In contrast, c.32A>T was associated with increased susceptibility

to HCV in women, with higher levels of viremia, more rapid selleck disease progression, and failure to respond to interferon-based HCV therapy.[107] TLR7-mediated IFN-α secretion is impaired in these women, while TLR7-mediated IL-6 production is preserved.[108] These data collectively demonstrate that TLR2, TLR4, and TLR7 gene SNP detection may eventually provide potential screening tools for adverse outcomes in HCV-infected patients,

guiding timing of therapy. However, further validation studies are warranted. Given the evidence for impairment of TLR function in HCV infection, restoration of TLR function through TLR agonists is a theoretically attractive approach for potential therapy. In particular, restoration of TLR3-, TLR7-, and TLR9-mediated NK cell and DC interferon secretion so as to improve antigen presentation and T-cell activation is an enticing target for therapy; these effects would not reduce immune responses against other infections, as may be seen if TLR inflammatory pathways were targeted. Importantly, TLR therapies may be less susceptible to viral resistance and broadly active against all HCV genotypes as they do not target HCV proteins directly. There is evidence that TLR7 agonists are effective at HCV suppression. Isotoribine successfully reduced serum HCV levels in phase I trials but unfortunately has been removed from further studies because of adverse events; other TLR7 agonists are under development.