title: The stability of secreted, acid-labile H77/JFH-1 hepatitis C virus (HCV) particles is altered by patient isolate genotype 1a p7 sequences.
abstract: Secreted infectious particles generated by the genotype 2a JFH-1 hepatitis C virus infectious clone are resistant to acidic pH, whereas intracellular virions remain acid-labile. Thus, JFH-1 particles are thought to undergo pH maturation as they are secreted from the cell. Here, we demonstrate that both infectious intracellular and secreted genotype 1a (H77)/JFH-1 chimaeric particles display enhanced acid sensitivity compared with JFH-1, although pH maturation still occurs upon release. Introduction of p7 sequences from genotype 1a infected HCV patients into the H77/JFH-1 background yielded variable effects on infectious particle production and sensitivity to small molecule inhibitors. However, two selected patient p7 sequences increased the acid stability of secreted, but not intracellular H77/JFH-1 particles, suggesting that p7 directly influences particle pH maturation via an as yet undefined mechanism. We propose that HCV particles vary in acid stability, and that this may be dictated by variations in both canonical structural proteins and p7.
authors: School of Molecular & Cellular Biology & Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT, United Kingdom.
authors: Elizabeth
authors: E
authors: Atkins
authors: Ranjitha
authors: R
authors: Tatineni
authors: Hui
authors: H
authors: Li
authors: David
authors: D
authors: Gretch
authors: Mark
authors: M
authors: Harris
authors: Stephen
authors: S
authors: Griffin
mesh_terms: D000143:Acids / Q000494:pharmacology*; D000595:Amino Acid Sequence; D002460:Cell Line; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D057074:Virus Release / Q000187:drug effects; D000086082:Viroporin Proteins
chemical_list: D000143:Acids; D014764:Viral Proteins; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins
keywords: DAA; DMEM; Drug resistance; Dulbecco's modified eagles medium; GAPDH; GT; HCC; HCV; IAV; Ion channel gating; M2; MeOH; NS; Natural virus variants; Particle acid stability; TM; Viroporin; direct-acting antivirals; genotype; glyceraldehyde 3-phosphate dehydrogenase; hepatitis C virus; influenza A virus; matrix protein 2; methanol; non-structural; nuclear hepatocellular carcinoma; reverse phase high performance liquid chromatography; rp-HPLC; trans-membrane; vATPase; vacuolar adenosine tri-phosphatase