Vaccination for Hepatitis C Virus

Closing in on an Evasive Target

John Halliday; Paul Klenerman; Eleanor Barnes


Expert Rev Vaccines. 2011;10(5):659-672. 

In This Article

HCV Diversity: Implications for Vaccine Development

Studies based on the molecular evolution of African and Asian HCVs suggest that HCV first appeared over 1000 years ago.[7] Subsequently, HCV evolved in discrete geographical regions giving rise to six distinct genotypes (1–6). These genotypes share a genetic homology of approximately 80% and are further subdivided into more than 100 subtypes.[8,9] In recent decades there has been a global epidemic of a few subtypes (1a, 1b, 3a, 2a and 4a) associated with intravenous drug use (IVDU) and modern medical practice. The HCV genotype not only has relevance in relation to geographic distribution but more importantly in determining response to current medical therapy.[10]

HCV is a particularly fastidious virus and has only been demonstrated reproducibly to replicate in the hepatocytes of humans and chimpanzees. It is a ssRNA virus with an enveloped virion belonging to the family Flaviviridae.[11] The positive-sense RNA genome is 9600 nucleotides in length. A single HCV polyprotein comprised of 3011 amino acids is translated from the genome and subsequently cleaved by cellular and viral proteases into three structural proteins (core, E1 and E2) and seven nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B).[12,13] The envelope proteins mediate viral cell entry by binding to a number of cell surface receptors (e.g., low-density lipoprotein receptor, CD81, scavenger receptor B1 and claudin).[14]

HCV mutates at nearly one nucleotide per replication cycle as a consequence of the poor fidelity of the NS5B viral polymerase (which lacks proofreading function). This, in conjunction with a short viral half-life and rapid turnover (just a few hours), results in a high genetic variability. Consequently, many distinct but closely related HCV variants (known as quasispecies) are typically found in each infected individual.[15] It is estimated that HCV viral diversity is ten-times greater than that found in HIV infection and this clearly represents a significant challenge to successful vaccine development.


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