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The ins and outs of hepatitis C virus entry and assembly

Nature Reviews Microbiology volume 11, pages 688–700 (2013)Cite this article

Subjects

Key Points

  • Hepatitis C virus (HCV) is an enveloped, positive-strand RNA virus. Unlike other enveloped RNA viruses, HCV particles interact with serum lipoproteins, which are important for the infectivity of HCV particles.

  • New structural information is available for E2 glycoprotein of the related pestiviruses. Common features of HCV and pestiviruses suggest that these viruses use an uncharacterized mechanism of viral fusion.

  • HCV particles enter cells via a multistep process involving numerous cell surface proteins, cellular processing of virus-associated lipoproteins, signal transduction events, clathrin-mediated internalization of the virus, and low-pH-induced membrane fusion.

  • HCV particle assembly occurs via budding into the ER. This process requires recently defined interactions between the viral structural and non-structural proteins.

  • Nascent HCV particles exit the cell via transit through the secretory pathway. During this process, HCV undergoes maturational events similar to those of serum lipoproteins.

Abstract

Hepatitis C virus, a major human pathogen, produces infectious virus particles with several unique features, such as an ability to interact with serum lipoproteins, a dizzyingly complicated process of virus entry, and a pathway of virus assembly and release that is closely linked to lipoprotein secretion. Here, we review these unique features, with an emphasis on recent discoveries concerning virus particle structure, virus entry and virus particle assembly and release.

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Figure 1: Structural aspects of HCV and related viruses.
Figure 2: HCV entry.
Figure 3: HCV assembly and secretion.

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Acknowledgements

The authors thank M. T. Catanese and Y. Modis for sharing data prior to publication and for helpful comments on the manuscript. B.D.L. is supported by grants from the US Public Health Service, National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID; grants AI076259, AI087925 and AI089826). C.M.R. is supported by NIAID (grants AI099284, AI072613, AI075099 and AI090055), the Office of the Director through the NIH Roadmap for Medical Research (grant DK085713), the National Cancer Institute (grant CA057973), The Rockefeller University Center for Clinical and Translational Science (grant UL1RR024143), the Center for Basic and Translational Research on Disorders of the Digestive System through the generosity of the Leona M. and Harry B. Helmsley Charitable Trust, the Greenberg Medical Research Institute and the Starr Foundation.

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Authors and Affiliations

  1. Department of Microbial Pathogenesis, Yale University, New Haven, 06536, Connecticut, USA

    Brett D. Lindenbach

  2. Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, 10012, New York, USA

    Charles M. Rice

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Glossary

Type I interferon

A class of cytokines that is induced by viral infection and interferes with viral replication. These cytokines include multiple interferon-α proteins, encoded by separate genes, as well as a single interferon-β.

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Genetic units that are capable of autonomous replication in a suitable host cell. A hepatitis C virus subgenomic replicon is a viral RNA that is less than genome length but still capable of autonomous replication.

Pleiomorphic

Heterogeneous in morphology, form or shape.

Buoyant density

A physical characteristic of an object, describing its tendency to float above liquids that have greater densities than the object. Thus, at equilibrium, the buoyant density of an object is equal to the density of the surrounding liquid. Buoyant densities are determined by using isopycnic ultracentrifugation.

Tetraspanin

A member of a family of related cell surface proteins that have four membrane- spanning domains. Tetraspanins contain a small amino-terminal extracellular domain and a large carboxy-terminal extracellular domain that contains a conserved motif of disulphide-bonded cysteine residues.

Tight junctions

Specialized plasma membrane compartments between two adjacent cells. These junctions are impermeable to small molecules and charged ions, thereby physically separating the apical and basoateral surfaces of cells. Also known as the zonula occludens.

Secretory pathway

A series of subcellular membrane-bound compartments that traffic proteins and small molecules from the inside to the outside of cells.

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Lindenbach, B., Rice, C. The ins and outs of hepatitis C virus entry and assembly. Nat Rev Microbiol 11, 688–700 (2013). https://doi.org/10.1038/nrmicro3098

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