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Journal of gastroenterology
11, 2024;59 (11): 1021-1036.

Single-molecule sequencing of the whole HCV genome revealed envelope deletions in decompensated cirrhosis associated with NS2 and NS5A mutations.

Kozue Yamauchi, Shinya Maekawa, Leona Osawa, Yasuyuki Komiyama, Natsuko Nakakuki, Hitomi Takada, Masaru Muraoka, Yuichiro Suzuki, Mitsuaki Sato, Shinichi Takano, Nobuyuki Enomoto
Author Information
  1. Kozue Yamauchi: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  2. Shinya Maekawa: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. maekawa@yamanashi.ac.jp. ORCID
  3. Leona Osawa: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  4. Yasuyuki Komiyama: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  5. Natsuko Nakakuki: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  6. Hitomi Takada: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  7. Masaru Muraoka: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  8. Yuichiro Suzuki: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  9. Mitsuaki Sato: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  10. Shinichi Takano: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
  11. Nobuyuki Enomoto: Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
PMID: 39225750 DOI: 10.1007/s00535-024-02146-3

Abstract

BACKGROUND: Defective hepatitis C virus (HCV) genomes with deletion of the envelope region have been occasionally reported by short-read sequencing analyses. However, the clinical and virological details of such deletion HCV have not been fully elucidated.
METHODS: We developed a highly accurate single-molecule sequencing system for full-length HCV genes by combining the third-generation nanopore sequencing with rolling circle amplification (RCA) and investigated the characteristics of deletion HCV through the analysis of 21 patients chronically infected with genotype-1b HCV.
RESULT: In 5 of the 21 patients, a defective HCV genome with approximately 2000 bp deletion from the E1 to NS2 region was detected, with the read frequencies of 34-77%, suggesting the trans-complementation of the co-infecting complete HCV. Deletion HCV was found exclusively in decompensated cirrhosis (5/12 patients), and no deletion HCV was observed in nine compensated patients. Comparing the amino acid substitutions between the deletion and complete HCV (DAS, deletion-associated substitutions), the deletion HCV showed higher amino acid mutations in the ISDR (interferon sensitivity-determining region) in NS5A, and also in the TMS (transmembrane segment) 3 to H (helix) 2 region of NS2.
CONCLUSIONS: Defective HCV genome with deletion of envelope genes is associated with decompensated cirrhosis. The deletion HCV seems susceptible to innate immunity, such as endogenous interferon with NS5A mutations, escaping from acquired immunity with deletion of envelope proteins with potential modulation of replication capabilities with NS2 mutations. The relationship between these mutations and liver damage caused by HCV deletion is worth investigating.

Keywords

Deletion Haplotype ISDR NS2 Quasispecies

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Grants

  1. JP23fk0210104/Japan Agency for Medical Research and Development
  2. JP23fk0210113/Japan Agency for Medical Research and Development
  3. JP23fk0210122/Japan Agency for Medical Research and Development
  4. JP23fk0210123/Japan Agency for Medical Research and Development
  5. JP24K11109/Japan Society for the Promotion of Science

MeSH Term

Humans
Viral Nonstructural Proteins
Hepacivirus
Liver Cirrhosis
Male
Female
Middle Aged
Hepatitis C, Chronic
Genome, Viral
Mutation
Aged
Sequence Deletion
Viral Envelope Proteins
Genotype
Adult
Nanopore Sequencing
RNA-Dependent RNA Polymerase

Chemicals

Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus
NS2 protein, Hepatitis C virus
Viral Envelope Proteins
RNA-Dependent RNA Polymerase
Journal Article Research Support, Non-U.S. Gov't

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