title: Limited naturally occurring escape in broadly neutralizing antibody epitopes in hepatitis C glycoprotein E2 and constrained sequence usage in acute infection.
abstract: Broadly neutralizing antibodies have been associated with spontaneous clearance of the hepatitis C infection as well as viral persistence by immune escape. Further study of neutralizing antibody epitopes is needed to unravel pathways of resistance to virus neutralization, and to identify conserved regions for vaccine design. All reported broadly neutralizing antibody (BNAb) epitopes in the HCV Envelope (E2) glycoprotein were identified. The critical contact residues of these epitopes were mapped onto the linear E2 sequence. All publicly available E2 sequences were then downloaded and the contact residues within the BNAb epitopes were assessed for the level of conservation, as well as the frequency of occurrence of experimentally-proven resistance mutations. Epitopes were also compared between two sequence datasets obtained from samples collected at well-defined time points from acute (<180days) and chronic (>180days) infections, to identify any significant differences in residue usage. The contact residues for all BNAbs were contained within 3 linear regions of the E2 protein sequence. An analysis of 1749 full length E2 sequences from public databases showed that only 10 out of 29 experimentally-proven resistance mutations were present at a frequency >5%. Comparison of subtype 1a viral sequences obtained from samples collected during acute or chronic infection revealed significant differences at positions 610 and 655 with changes in residue (p<0.05), and at position 422 (p<0.001) with a significant difference in variability (entropy). The majority of experimentally-described escape variants do not occur frequently in nature. The observed differences between acute and chronically isolated sequences suggest constraints on residue usage early in infection.
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. Electronic address: c.rodrigo@unsw.edu.au.
authors.forename: Chaturaka
authors.initials: C
authors.lastname: Rodrigo
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Walker
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Preston
authors.initials: P
authors.lastname: Leung
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Auda A
authors.initials: AA
authors.lastname: Eltahla
authors.affiliation: The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Grebely
authors.affiliation: The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.affiliation: The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Tanya
authors.initials: T
authors.lastname: Applegate
authors.affiliation: Department of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Page
authors.affiliation: Department of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Sunita
authors.initials: S
authors.lastname: Dwivedi
authors.affiliation: CRCHUM, Université de Montréal, Montreal, QC, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Bruneau
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
authors.forename: Meghan D
authors.initials: MD
authors.lastname: Morris
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Cox
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: William
authors.initials: W
authors.lastname: Osburn
authors.affiliation: Harvard Medical School, Boston, MA, USA.
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Center for Infection and Immunity Amsterdam, Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands.
authors.forename: Janke
authors.initials: J
authors.lastname: Schinkel
authors.affiliation: CRCHUM, Université de Montréal, Montreal, QC, Canada.
authors.forename: Naglaa H
authors.initials: NH
authors.lastname: Shoukry
authors.affiliation: Harvard Medical School, Boston, MA, USA.
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
authors.affiliation: The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Maher
authors.affiliation: Burnet Institute, Melbourne, VIC, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Hellard
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Center for Infection and Immunity Amsterdam, Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands; GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Prins
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Fabio
authors.initials: F
authors.lastname: Luciani
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Lloyd
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Rowena A
authors.initials: RA
authors.lastname: Bull
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000235:genetics; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015870:Gene Expression; D016174:Hepacivirus / Q000737:chemistry / Q000235:genetics; D018937:Hepatitis C Antibodies / Q000737:chemistry* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D057131:Immune Evasion; D008958:Models, Molecular; D059645:Mutation Rate; D017433:Protein Structure, Secondary; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D018937:Hepatitis C Antibodies; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus
keywords: Broadly neutralizing antibodies; Epitopes; Glycoprotein E2; Hepatitis C; InC(3) collaborative