New insights into HCV replication: potential antiviral targets

Abstract

The ultimate goal of hepatitis C virus (HCV) treatment is the eradication of the virus. Ongoing research continues to add to knowledge of the HCV life cycle, revealing new potential viral and host targets for the development of therapy. Understanding of HCV was initially hampered by the inability to achieve viral replication in cell culture. Advances such as the HCV replicon and complete cell culture systems, however, have permitted rapid growth in knowledge and accelerated testing of candidate antiviral agents. Among potential targets are viral entry factors, including scavenger receptor type B1 (SR-B1) and CD81, as well as neutralizing antibodies against the viral glycoproteins. Popular targets related to translation and replication are the NS3/4A protease (inhibited by telaprevir and boceprevir) and the NS5B polymerase, as well as the NS2/3 autoprotease, the NS3 helicase, and nonenzymatic targets such as NS4B and NS5A proteins. Host targets are also available, including microRNAs and cyclophilins. This article summarizes a presentation by Charles M. Rice, PhD, at the IAS-USA live continuing medical education course, Management of Hepatitis C Virus in the New Era: Small Molecules Bring Big Changes, held in New York City in April 2011.

Conflict of interest statement

Financial Disclosure: Dr Rice has served as a consultant or scientific advisor to Genentech Inc, GlaxoSmithKline, iTherX, Inc, Merck & Co, Inc, and Novartis Vaccines and Diagnostics. He is a major stock shareholder for Apath, LLC. Dr Murray has no relevant financial affiliations to disclose. Her spouse is employed by Novartis.

Figures

Figure 1.

Delineation of hepatitis C virus (HCV) genome organization and polyprotein processing. Schematic shows structural proteins, nonstructural proteins, and enzymatic activities required for cleaving the polyprotein. Adapted from Bartenschlager et al, Grakoui et al, and Hijikata et al.

Figure 2.

Current model of hepatitis C virus entry into the hepatocyte. GAG indicates glu-cosaminoglycan; LDLR, low-density lipoprotein receptor; SR-B1, scavenger receptor type B1; CLDN-1, claudin-1; OCLN, occludin. Adapted from an animated slide from Shihyun You, PhD, and Charles Rice, PhD.

Figure 3.

Hepatitis C virus proteins and functions. ER indicates endoplasmic reticulum. Scissors indicate cleavage by host enzymes, arrows represent processing by viral proteases. Adapted from Moradpour et al.