Recombination in Hepatitis C Virus: Identification of Four Novel Naturally Occurring Inter-Subtype Recombinants

Abstract

Recombination in Hepatitis C virus (HCV) is considered to be rare. In this study, we performed a phylogenetic analysis of 1278 full-length HCV genome sequences to identify potential recombination events. Nine inter-genotype recombinants were identified, all of which have been previously reported. This confirms the rarity of inter-genotype HCV recombinants. The analysis also identified five inter-subtype recombinants, four of which are documented for the first time (EU246930, EU246931, EU246932, and EU246937). Specifically, the latter represent four different novel recombination types (6a/6o, 6e/6o, 6e/6h, and 6n/6o), and this was well supported by seven independent methods embedded in RDP. The breakpoints of the four novel HCV recombinants are located within the NS5B coding region and were different from all previously reported breakpoints. While the locations of the breakpoints identified by RDP were not identical, they are very close. Our study suggests that while recombination in HCV is rare, this warrants further investigation.

Mixed HCV infection and reinfection in people who inject drugs—impact on therapy

“…51 Recombination between divergent HCV strains (defined as viruses of distinct genotypes or subtypes)-which also contributes to viral diversity and confers the ability to rapidly adapt and escape the selection pressures of host immune responses and antiviral therapy-has also been demonstrated, albeit uncommonly. [52][53][54][55][56][57] Similarly, across ethnically and geographically diverse populations, the constant evolution of HCV has led to considerable global genetic diversity.…”

“…11,[14][15][16]18,19,24,25,[105][106][107][108] Indirect evidence of mixed HCV infection has also been provided from the identification of genomic recombination of HCV in patient blood samples, which can confer drug-resistance, implying the coexistence of two strains within a single cell. [54][55][56][57] Although genetic recombination seems to be rare, the rate of recombination might be underestimated, as sensitive detection methods that require amplification of at least two distant genomic regions are not commonly used. The considerable variation in the prevalence of mixed HCV infection between studies is probably related to a number of factors, including differences in study design (for example, frequency and duration of study follow-up), study populations (age, sex and high-risk behaviours such as drug injection) and the sensitivity of the laboratory methodologies used for detection.…”

Hepatitis C virus genetic variability and evolution

“…In addition, the sequences showed a very dissimilar size, exhibiting relatively short segments of one subtype embedded within a genome of the other subtype [49] . The most recent description of intersubtype recombinant forms involves genotype 6, and these were identified thanks to full-genome sequence analysis [144] . The remaining three cases of intersubtypic RFs reported have only been partially characterised at the genome level [49] .…”

“…Finally, despite recombination events between different genotypes/subtypes co-infecting the same patient are probably easier to detect, they are less likely to occur, since the strains of different subtypes differ more between them than between those from the same subtype; this would imply a lower probability of template switching and moreover, if a recombination event does indeed happen, it will likely generate recombinant sequences less viable than the parental ones. Some or even all these factors acting in concert might explain why the frequency of recombinant HCV sequences reported to date is so low [49,111,[124][125][126][127][128][129][130][131][132][133][134][135][136][137][140][141][142][143][144][145][146][147] . How relevant recombination for HCV long term evolution and its incidence in HCV infection is, has not been thoroughly investigated yet, but these findings support a potentially significant role for recombination by creating genetic variation through the reshuffling of independent variants [146] .…”

On the relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus genetic diversity

“…; Shi et al . ) and therefore have highlighted the influence of clonal interference in this context (Strelkowa & Lässig ). In contrast, recombination is common in DNA viruses (Fleischmann ) which should lessen the influence of clonal interference and increase rates of adaptation (Miralles et al .…”