title: Mapping the genomic diversity of HCV subtypes 1a and 1b: Implications of structural and immunological constraints for vaccine and drug development.
abstract: Despite significant progress in hepatitis C (HCV) treatment, global viral eradication remains a challenge. An in-depth map of its genome diversity within the context of structural and immunological constraints could contribute to the design of pan-genotypic antivirals and preventive vaccines. For such analyses, extensive information is only available for the highly prevalent HCV genotypes (GT) 1a and 1b. Using 647 GT1a and 408 GT1b full-genome sequences obtained from the Los Alamos database, we found that respectively 3 per cent and 82 per cent of all codon positions are under positive and negative selective pressure, suggesting variation mainly accumulates due to random genetic drift. An association between conservation and both structured RNA and secondary protein structures confirmed the important role of structural elements at nucleotide and at amino acid level. Remarkably, CD8+T-cell epitopes in HCV GT1a were significantly more conserved, while at the same time containing more sites under positive selection. Similarly, CD4+T-cell epitopes were significantly more conserved in both HCV subtypes, but under less positive selective pressure in GT1b and more negative selective pressure in GT1a. In contrast, B-cell epitopes in both subtypes were less conserved and under less stringent negative selection. These findings argue against immune selective pressure as the main force of between-host diversifying evolution. Despite its high variability, HCV is under strict evolutionary constraints, most probably to keep its genes and proteins functional during the replication cycle. These are encouraging findings for vaccine and drug design, which could consider these newly established genetic diversity profiles.
authors: KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Lize
authors: L
authors: Cuypers
authors: KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium; Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors: Guangdi
authors: G
authors: Li
authors: Department of Medicine II, Freiburg University Medical Center, University of Freiburg, Freiburg, Germany.
authors: Christoph
authors: C
authors: Neumann-Haefelin
authors: KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium; Department of Electrical Engineering ESAT, STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, KU Leuven, University of Leuven, Kasteelpark Arenberg 10, B-3001 Heverlee, Belgium.
authors: Supinya
authors: S
authors: Piampongsant
authors: Artificial Intelligence Lab, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Pieter
authors: P
authors: Libin
authors: KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Kristel
authors: K
authors: Van Laethem
authors: KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium; Center for Global Health and Tropical Medicine, Microbiology Unit, Institute for Hygiene and Tropical Medicine, University Nova de Lisboa, Rua da Junqueira 100, Lisbon, 1349-008, Portugal.
authors: Anne-Mieke
authors: AM
authors: Vandamme
authors: KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Kristof
authors: K
authors: Theys
keywords: HCV GT1a and GT1b; RNA structure; T- and B-cell epitopes; conservation; protein secondary structure; selective pressure