Abstract
Treatment with pan-genotypic direct-acting antivirals, targeting different viral proteins, is the best option for clearing hepatitis C virus (HCV) infection in chronically infected patients. However, the diversity of the HCV genome is a major obstacle for the development of antiviral drugs, vaccines, and genotyping assays. In this large-scale analysis, genome-wide diversity and selective pressure was mapped, focusing on positions important for treatment, drug resistance, and resistance testing. A dataset of 1415 full-genome sequences, including genotypes 1–6 from the Los Alamos database, was analyzed. In 44% of all full-genome positions, the consensus amino acid was different for at least one genotype. Focusing on positions sharing the same consensus amino acid in all genotypes revealed that only 15% was defined as pan-genotypic highly conserved (≥99% amino acid identity) and an additional 24% as pan-genotypic conserved (≥95%). Despite its large genetic diversity, across all genotypes, codon positions were rarely identified to be positively selected (0.23%–0.46%) and predominantly found to be under negative selective pressure, suggesting mainly neutral evolution. For NS3, NS5A, and NS5B, respectively, 40% (6/15), 33% (3/9), and 14% (2/14) of the resistance-related positions harbored as consensus the amino acid variant related to resistance, potentially impeding treatment. For example, the NS3 variant 80K, conferring resistance to simeprevir used for treatment of HCV1 infected patients, was present in 39.3% of the HCV1a strains and 0.25% of HCV1b strains. Both NS5A variants 28M and 30S, known to be associated with resistance to the pan-genotypic drug daclatasvir, were found in a significant proportion of HCV4 strains (10.7%). NS5B variant 556G, known to confer resistance to non-nucleoside inhibitor dasabuvir, was observed in 8.4% of the HCV1b strains. Given the large HCV genetic diversity, sequencing efforts for resistance testing purposes may need to be genotype-specific or geographically tailored.
Highlights
Despite 20 years of intensive research, a vaccine to prevent infection with the hepatitis C virus (HCV) remains elusive, while two million new HCV infections are estimated to occur worldwide every year [1]
Given the clinical and epidemiological importance especially in this new direct acting antiviral (DAA) era, this study aimed to provide a detailed mapping of HCV genomic diversity and to determine the extent of pan-genotype residue conservation, using a large sequence dataset encompassing HCV genotypes 1–6
If resistance testing is cost effective at a cut-off of 5%, NS5A variant 30Q should be monitored in HCV1b infected patients treated with NS5A inhibitor daclatasvir [64], since our analysis revealed that 7% of the HCV1b strains harbored amino acid Q
Summary
Despite 20 years of intensive research, a vaccine to prevent infection with the hepatitis C virus (HCV) remains elusive, while two million new HCV infections are estimated to occur worldwide every year [1]. A preventive vaccine would need to induce broad reactive immunity in order to cope with the extensive genomic diversity of HCV [3]. HCV diversity is classified into seven genetically distinct genotypes (HCV 1–7) [4] that differ by more than 30% at nucleotide (NT) level, and into more than 50 subtypes that differ between 15% and 25% at nucleotide level within genotypes [5,6]. Substantial differences exist in the geographic distribution of HCV genotypes, with genotypes 1, 2, and 3 circulating worldwide, with different predominance according to geographical areas [7]. A major barrier for the development of vaccines, broadly active antivirals, and assays, is the high genetic diversity of HCV and its potential to quickly adapt to different environments [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
