Hepatitis C virus (HCV) infection afflicts more than 170 million people worldwide, with the great majority of patients with acute hepatitis C developing chronic HCV infection. It can ultimately result in liver cirrhosis, hepatic failure or hepatocellular carcinoma, which are responsible for hundreds of thousands of deaths each year. Despite the discovery of HCV over 15 years ago, our knowledge of the HCV lifecycle has been limited by our inability to grow the virus in cell culture, as well as by the lack of small-animal models of HCV infection. Nevertheless, data accumulated through the use of multiple in vitro and in vivo study systems have provided a general picture of the biology of HCV, although sometimes with contradictory results. Herein, we summarize our current understanding of the HCV genome and how its structure and encoded gene products, in a complex interplay with host cell factors, might orchestrate a productive viral lifecycle while evading the scrutiny of the host immune system. The recently developed robust in vitro HCV infection systems should help fill in some of the gaps in understanding the HCV lifecycle in the next few years.
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