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Cellular Determinants of Hepatitis C Virus Assembly, Maturation, Degradation, and Secretion

Pablo Gastaminza,¹ Guofeng Cheng,¹ Stefan Wieland,¹ Jin Zhong,^1, Wei Liao,² and Francis V. Chisari^1*

Division of Experimental Pathology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,¹ Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093²

Received 16 September 2007/ Accepted 3 December 2007

Intracellular infectious hepatitis C virus (HCV) particles display a distinctly higher buoyant density than do secreted virus particles, suggesting that the characteristic low density of extracellular HCV particles is acquired during viral egress. We took advantage of this difference to examine the determinants of assembly, maturation, degradation, and egress of infectious HCV particles. The results demonstrate that HCV assembly and maturation occur in the endoplasmic reticulum (ER) and post-ER compartments, respectively, and that both depend on microsomal transfer protein and apolipoprotein B, in a manner that parallels the formation of very-low-density lipoproteins (VLDL). In addition, they illustrate that only low-density particles are efficiently secreted and that immature particles are actively degraded, in a proteasome-independent manner, in a post-ER compartment of the cell. These results suggest that by coopting the VLDL assembly, maturation, degradation, and secretory machinery of the cell, HCV acquires its hepatocyte tropism and, by mimicry, its tendency to persist.

Published ahead of print on 19 December 2007.

Present address: Viral Hepatitis Unit, Institut Pasteur-Shanghai, 225 South Chongqing Rd., Shanghai, China 200025.