Hepatitis C virus genotype 1 and 2 recombinant genomes and the phylogeographic history of the 2k/1b lineage

Abstract

Recombination is an important driver of genetic diversity, though it is relatively uncommon in hepatitis C virus (HCV). Recent investigation of sequence data acquired from HCV clinical trials produced twenty-one full-genome recombinant viruses belonging to three putative inter-subtype forms 2b/1a, 2b/1b, and 2k/1b. The 2k/1b chimera is the only known HCV circulating recombinant form (CRF), provoking interest in its genetic structure and origin. Discovered in Russia in 1999, 2k/1b cases have since been detected throughout the former Soviet Union, Western Europe, and North America. Although 2k/1b prevalence is highest in the Caucasus mountain region (i.e., Armenia, Azerbaijan, and Georgia), the origin and migration patterns of CRF 2k/1b have remained obscure due to a paucity of available sequences. We assembled an alignment which spans the entire coding region of the HCV genome containing all available 2k/1b sequences (>500 nucleotides; n = 109) sampled in ninteen countries from public databases (102 individuals), additional newly sequenced genomic regions (from 48 of these 102 individuals), unpublished isolates with newly sequenced regions (5 additional individuals), and novel complete genomes (2 additional individuals) generated in this study. Analysis of this expanded dataset reconfirmed the monophyletic origin of 2k/1b with a recombination breakpoint at position 3,187 (95% confidence interval: 3,172–3,202; HCV GT1a reference strain H77). Phylogeography is a valuable tool used to reveal viral migration dynamics. Inference of the timed history of spread in a Bayesian framework identified Russia as the ancestral source of the CRF 2k/1b clade. Further, we found evidence for migration routes leading out of Russia to other former Soviet Republics or countries under the Soviet sphere of influence. These findings suggest an interplay between geopolitics and the historical spread of CRF 2k/1b.

The evolutionary history of hepaciviruses

“…However, the spatial component of prevalence can be also crucial in shaping virus diversity. Hepacivirus spatial structure has so far been investigated only at an intraspecies level, for instance, within HCV genotypes (Markov et al 2009;Iles et al 2014;Hostager et al 2019).…”

Prevalence of resistance-associated substitutions and phylogenetic analysis of hepatitis C virus infection in Russia

“…HCV recombination events are rare in vivo and recombinant HCV strains are often non-viable in vitro ( Giannini et al, 1999 ;Viazov et al, 20 0 0 ). The circulating recombinant form 2k/1b was first identified in Saint Petersburg ( Kalinina et al, 2002 ;Susser et al, 2017 ), and phylogeographic analysis has suggested that the 2k/1b CRF originated in Russia, with more recent introductions seen in countries outside of this region ( Hostager et al, 2019 ) such as Armenia, Azerbaijan, Georgia, Germany, and Ukraine. Patients infected with HCV 2k/1b have been treated successfully with pan-genotypic DAAs such as glecaprevir/pibrentasvir ( Zubkin et al, 2019 ) and SOF-based regimens ( Hedskog et al, 2015 ;Susser et al, 2017 ).…”

Temporal trends of hepatitis C virus transmission in internally displaced people who inject drugs in Odessa, Ukraine

“…In this study, we report much higher prevalence of HCV infection with the 1a (25%) subtype, and comparable levels of infection with 1b (40%) and 3a (35%) within IDPWID in Odessa. The HCV subtype 1b dominates epidemics in the neighboring Russian Federation (1a – 2.1%; 1b – 52.8%; 3 – 36.3%) and several post-Soviet countries, such as Uzbekistan and Azerbaijan, whilst 1a is more commonly found in western Europe [9, 29]. Higher 1a prevalence amongst HIV co-infected patients compared to the general population has been linked to IDU mediated transmission elsewhere [30], and thus is expected in our study population.…”