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8 Charles M Rice Rockefeller Univ, New York, NY, USA |
Background: Even with the current treatment, hepatitis C continues to be incurable in many patients. This need has catalyzed an intense effort in the academic and private sectors on basic HCV biology and specific antiviral compounds. One roadblock to these efforts was the lack of a robust cell culture system for studying HCV. In 1999, the first HCV subgenomic RNA replicons were reported, and further studies have extended this system to produce efficient subgenomic and full-length replicons from multiple subtypes and 2 genotypes, highly permissive cell substrates, and a series of convenient reporters for rapid screening and evaluation of inhibitors. These systems have been invaluable for dissecting the molecular details of HCV RNA replica These systems can be used to target key lifecycle processes including translation, RNA replication, and entry, and to identify mutations conferring resistance to antiviral drugs. Conclusions: Although these are powerful systems, concern remains that they may not truly represent replication in vivo. For example, replication of HCV RNA in cell culture often requires adaptive mutations in the replicase that are deleterious for replication in vivo. Nonetheless, proof-of-concept data are emerging for compounds with potent replicon inhibition in cell culture that are also highly effective in vivo. While these results are encouraging, continued efforts are needed to develop replicons for other HCV genotypes, complete infection systems, and animal models to assess in vivo efficacy and emergence of resistance. On the vaccine front, despite early pessimism, evidence is emerging for protective immunity in resolved natural infections and in experimental prophylactic vaccines tested in chimpanzees.
