Hepatitis C virus cell entry: role of lipoproteins and cellular receptors

Abstract

Hepatitis C virus (HCV), a major cause of chronic liver disease, is a single-stranded positive sense virus of the family Flaviviridae. HCV cell entry is a multi-step process, involving several viral and cellular factors that trigger virus uptake into the hepatocyte. Tetraspanin CD81, human scavenger receptor SR-BI, and tight junction molecules Claudin-1 and occludin are the main receptors that mediate HCV entry. In addition, the virus may use glycosaminoglycans and/or low density receptors on host cells as initial attachment factors. A unique feature of HCV is the dependence of virus replication and assembly on host cell lipid metabolism. Most notably, during HCV assembly and release from the infected cells, virus particles associate with lipids and very-lowdensity lipoproteins. Thus, infectious virus circulates in patient sera in the form of triglyceride-rich particles. Consequently, lipoproteins and lipoprotein receptors play an essential role in virus uptake and the initiation of infection. This review summarizes the current knowledge about HCV receptors, mechanisms of HCV cell entry and the role of lipoproteins in this process. IntroductionHepatitis C virus (HCV) infection is a major world health problem; it has a prevalence of about 2 %, representing 130-170 million infected people worldwide (Shepard et al., 2005). In most cases (60-85 %), HCV infection progresses to chronic liver disease, which can lead to liver cirrhosis and hepatocarcinoma (Shepard et al., 2005). The current therapy, based on the combination of pegylated interferon with ribavirin, is effective in only 50-80 % of the patients, depending on the virus genotype, and has several serious side effects (Fried et al., 2002; Manns et al., 2001; Keam & Cvetkovic, 2008;Pawlotsky, 2006). A better understanding of the mechanisms leading to the initiation of infection is essential for the development of new therapeutic approaches targeting the early stage of the HCV replication cycle.HCV is a small, enveloped virus belonging to the family Flaviviridae (genus Hepacivirus). HCV has a singlestranded positive sense RNA genome of about 9.6 kb, encoding a polyprotein of about 3000 amino acids (aa), which is cleaved into structural (core, E1 and E2) and nonstructural (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins by host and viral proteases. Structural proteins form viral particles with the help of p7 and NS2, whereas non-structural proteins NS3 to NS5B are involved in genome replication (reviewed by Bartenschlager et al., 2004;Bartenschlager & Sparacio, 2007;Brass et al., 2006;Penin et al., 2004). The putative infectious virus particle is composed of a nucleocapsid or ribonucleoprotein complex bearing the HCV genome; this inner structure is surrounded by a phospholipid bilayer, into which E1 and E2 envelope glycoproteins are anchored. However, infectious HCV particles become tightly associated with verylow-density lipoproteins (VLDL) during virus assembly and are (co-)secreted with VLDL, although the exact nature of this association remains unclear (Gas...

Host–virus interactions during hepatitis C virus infection: a complex and dynamic molecular biosystem

“…driven research in model systems using modern biochemical and cell biological methods. These methods have uncovered various aspects of the entire lifecycle of HCV including interactions of envelope proteins E1 and E2 with various receptors that are required for HCV entry, [25][26][27][28][29][33][34][35][36][37][38][39][40][41][42] association of HCV proteins and replication complexes with modified membrane compartments, 5,13 modulation of host cell function including misfolded protein response pathway 51 and lipid metabolism, 48,[52][53][54][55][56] interactions of HCV with PKR and the RIG-I pathway for evasion of an immune response, [57][58][59][60] association of the core protein with lipid droplets, 45,52,61 and interactions of HCV with components of the VLDL pathway for viral assembly and secretion. 46,47 All of these discoveries help us to better understand the viral lifecycle, the evolution of HCV, and the reasons for target specificity or tissue tropism; moreover, they point to novel strategies for combating HCV.…”

“…Recently it has been established that the E1 and E2 viral proteins interact with four known host receptors CD81, claudin-1, SRB-1 and occludin and their interaction can also be mediated by GAGs, the LDL receptor, and both DC and liver cell specific-SIGN. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] The next step involves the fusion of the virion particle with membranes of the host cell and subsequent uncoating and release of the components of the virion particle that include the positive strand HCV genomic RNA, some HCV non-structural proteins, including NS5A, and, in some cases, host proteins, including low density lipoproteins (LDLs). 25,28,29 The HCV RNA then moves to ribosomes where the HCV polypeptide is translated and processed as previously mentioned.…”

Hepatitis c virus and host cell lipids: An intimate connection

“…78,79 In addition to the lipoprotein receptors, further cell-surface molecules including glycosaminoglycans, the tetraspanin CD81 and two tight junction proteins -claudin-1 and occludin-are essential for internalization of the virus (reviewed in ref. 80).…”

Experimental models to study the immunobiology of hepatitis C virus

“…These models have been instrumental in identifying host cell receptors for HCV infection and the study of neutralizing antibodies (reviewed by Burlone & Budkowska, 2009;Stamataki et al, 2008). However, they are not of use for studies of innate and adaptive immune responses and therefore are not discussed in this review.…”