Studying Hepatitis C Virus: Making the Best of a Bad Virus

Abstract

2An estimated 3% of the world population is infected with hepatitis C virus (HCV) (5,232). In most infected individuals, this remarkable RNA virus evades the immune system and establishes a chronic infection that can lead to cirrhosis, liver cancer, and death. While advances have been made in treating HCV, the current therapy, a combination of pegylated alpha interferon and ribavirin, is poorly tolerated and is effective in only 50% of genotype 1-infected patients (reviewed in reference 53). The quest for new HCV therapies has driven research in academia and industry, which has led to significant progress in understanding basic virus replication mechanisms and in developing specific candidate antiviral compounds. In this minireview, we highlight recent advances in cell culture model systems used to study HCV and describe new insights into the virus life cycle that have been gleaned from these and other recent studies. This review is limited in scope to recent developments in HCV biology and is by no means comprehensive. Throughout the article, we have attempted to direct the reader to a number of high-quality review articles covering various aspects of HCV biology in greater detail.

Translation and replication of hepatitis C virus genomic RNA depends on ancient cellular proteins that control mRNA fates

“…From these, SLIII is proposed to interact with the 40S ribosomal subunits thus playing a key role in translation initiation. The SLII and SLIII stem loops function in replication as well (13,15). Electromobility shift analysis showed that the SLIII was both necessary and sufficient for binding of the LSm1-7 ring to the 5ЈUTR region (Fig.…”

“…The HCV 3ЈUTR consists of a variable region, a poly (U/UC) tract and a highly conserved terminal region termed 3ЈX tail that consists of 3 stem loop structures (13). Importantly, the 3ЈUTR is not only required for replication but also for efficient translation (16).…”

Hepatitis C Virus NS5A Protein Is a Substrate for the Peptidyl-prolyl cis/trans Isomerase Activity of Cyclophilins A and B

“…The HCV viral genome (ϳ9.6 kb) codes for a unique polyprotein of ϳ3000 amino acids (recently reviewed in Refs. [2][3][4]. Following processing via viral and cellular proteases, this polyprotein gives rise to at least 10 viral proteins, divided into structural (core, E1, and E2 envelope glycoproteins) and nonstructural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B).…”

Role of Phosphatidylinositol 4-Phosphate (PI4P) and Its Binding Protein GOLPH3 in Hepatitis C Virus Secretion

“…HCV is a major cause of various liver diseases such as liver steatosis, fibrosis, and cirrhosis, which can eventually progress into hepatocellular carcinoma (2). HCV replicates within the ribonucleoprotein complexes assembled on the ER-derived membranous structures termed "membranous webs" (3)(4)(5). The translation of the positive-strand HCV RNA on the ER is facilitated by an internal ribosome entry site in its 5Ј-UTR, generating a 3000-amino acid polyprotein which is co-and post-translationally cleaved by viral and cellular proteases to yield structural and non-structural viral proteins (2,4).…”

“…HCV replicates within the ribonucleoprotein complexes assembled on the ER-derived membranous structures termed "membranous webs" (3)(4)(5). The translation of the positive-strand HCV RNA on the ER is facilitated by an internal ribosome entry site in its 5Ј-UTR, generating a 3000-amino acid polyprotein which is co-and post-translationally cleaved by viral and cellular proteases to yield structural and non-structural viral proteins (2,4). HCV infection alters host lipid metabolism to facilitate enrichment of lipids that usually manifest in the accumulation of intracellular lipid droplets or hepatic steatosis (6 -8).…”