Comparative analysis of the molecular mechanisms of recombination in hepatitis C virus

Andrea Galli, Jens Bukh
2014 Trends in Microbiology  
Genetic recombination is an important evolutionary mechanism for RNA viruses. The significance of this phenomenon for hepatitis C virus (HCV) has recently become evident, with the identification of circulating recombinant forms in HCV-infected individuals and by novel data from studies permitted by advances in HCV cell culture systems and genotyping protocols. HCV is readily able to produce viable recombinants, using replicative and non-replicative molecular mechanisms. However, our knowledge
more » ... the required molecular mechanisms remains limited. Understanding how HCV recombines might be instrumental for a better monitoring of global epidemiology, to clarify the virus evolution, and evaluate the impact of recombinant forms on the efficacy of oncoming combination drug therapies. For the latter, frequency and location of recombination events could affect the efficacy of multidrug regimens. This review will focus on current data available on HCV recombination, also in relation to more detailed data from other RNA viruses. Genetic recombination in RNA viruses HCV is an important human pathogen, causing an estimated 180 million chronic infections and annually 3-4 million new infections worldwide [1]. Infected individuals are at increased risk of developing chronic liver diseases, including cirrhosis and hepatocellular carcinoma [2]. HCV is a single-stranded, positive-sense RNA virus, with a genome of around 9600 nucleotides that contains one long open reading frame (ORF) flanked by two distinct untranslated regions. The ORF encodes a single polyprotein that is cleaved by viral and cellular proteases into structural (core, E1, E2) and nonstructural (p7, NS2, NS3, NS4A and B, NS5A and B) proteins. Due to its extensive genetic heterogeneity, HCV has been classified into seven major genotypes (see Glossary) with genomes differing between 25% and 30% at the nucleotide and amino acid level. Genotypes are further divided into subtypes that typically diverge by more than 15%. HCV is classified as a member of the family Flaviviridae, genus Hepacivirus [3]. The genera Pestivirus (e.g., bovine viral diarrhea virus, BVDV; classical swine fever virus, CSFV), Flavivirus (e.g., dengue virus, yellow fever Review Glossary Co-infection: simultaneous infection of the host or target cell by two or more strains of the same virus. More broadly, it can indicate infection of the host by different viruses, such as HCV and hepatitis B virus in hepatocytes. Copy-choice recombination: a recombination model according to which recombinant molecules are generated by the strand switching activity of the viral polymerases. During synthesis of novel genomic strands, the nascent molecule can be transferred to a different template thus producing a chimeric genome. Genotype: a group of phylogenetically closely related viruses, defined by its genetic distance from other genotypes. HCV genotypes diverge around 30% from each other at the nucleotide level. In HIV classification, the term 'group' is used instead of genotype for the same level of correlation [91, 92] . Inter-genotype recombination: recombination occurring between viral strains belonging to different genotypes. Intra-genotype/inter-subtype recombination: recombination occurring between viral strains belonging to the same genotype but different subtypes. Intra-subtype recombination: recombination occurring between viral strains belonging to the same subtype. In HCV classification, such strains would typically differ around 5% at the nucleotide level [57] . Random breakage-rejoining recombination: a recombination model according to which recombinant genomes can be generated by random breakage and ligation of different genomic molecules. Breaks generated by mechanical forces or enzymatic activity produce a population of genomic fragments of different origin with compatible ends. Subsequently, cellular ligases or selfligation can randomly rejoin different fragments thus producing chimeric genomes. Replicon system: a cell system in which a sub-genomic or, less commonly, fulllength viral RNA is transfected into permissive cells and leads to viral RNA replication and production of viral proteins. Most sub-genomic replicons also carry a selectable marker gene to facilitate isolation of replicating cells. Despite several HCV full-length replicons being fully replication competent, consistent particle release could not be achieved with these systems [57] . Sequence homology: a measure of the level of evolutionary correlation between DNA sequences. Highly homologous sequences share a common ancestor. It is commonly, although incorrectly, used as a synonym for sequence similarity [93] . Subtype: a group of phylogenetically highly related viruses, clustering within a known genotype, defined by its genetic distance from other subtypes. In general, HCV subtypes diverge at least 15% from each other at the nucleotide level [91] . Super-infection: separate subsequent infections of the host or target cell by two or more different strains of the same virus. Super-infection exclusion: cellular mechanism(s) that prevent(s) re-infection of an already infected target cell by the same virus. 0966-842X/$ -see front matter ß
doi:10.1016/j.tim.2014.02.005 pmid:24636243 fatcat:kohzrtlp4rgbvowougbf4upr5m