Hepatitis C virus (HCV)
infection is a significant public health problem with over 170,000,000 chronic carriers and
infection rates increasing worldwide. Chronic HCV
infection is one of the leading causes of
hepatocellular carcinoma which was estimated to result in ∼10,000 deaths in the United States in the year 2011. Current treatment options for HCV
infection are limited to PEG-ylated
interferon alpha (IFN-α), the
nucleoside ribavirin and the recently approved HCV
protease inhibitors telaprevir and
boceprevir. Although showing significantly improved efficacy over the previous
therapies, treatment with
protease inhibitors has been shown to result in the rapid emergence of drug-resistant virus. Here we report the activity of two
proteins, originally isolated from natural product extracts, which demonstrate low or sub-nanomolar in vitro activity against both genotype I and genotype II HCV. These
proteins inhibit viral infectivity, binding to the HCV envelope
glycoproteins E1 and E2 and block viral entry into human hepatocytes. In addition, we demonstrate that the most potent of these agents, the
protein griffithsin, is readily bioavailable after
subcutaneous injection and shows significant in vivo efficacy in reducing HCV viral titers in a mouse model system with engrafted human hepatocytes. These results indicate that HCV viral entry inhibitors can be an effective component of anti-HCV
therapy and that these
proteins should be studied further for their therapeutic potential.