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Deep mutational scanning of hepatitis B virus reveals a mechanism for cis-preferential reverse transcription.
Yu, Yingpu; Kass, Maximilian A; Zhang, Mengyin; Youssef, Noor; Freije, Catherine A; Brock, Kelly P; Aguado, Lauren C; Seifert, Leon L; Venkittu, Sanjana; Hong, Xupeng; Shlomai, Amir; de Jong, Ype P; Marks, Debora S; Rice, Charles M; Schneider, William M.
Affiliation
  • Yu Y; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • Kass MA; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Department of Infectious Diseases, Molecular Virology, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany.
  • Zhang M; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • Youssef N; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Organismic and Evolutionary Biology, Broad Institute of MIT and Harvard, Harvard University, Cambridge, MA 02138, USA.
  • Freije CA; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • Brock KP; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Organismic and Evolutionary Biology, Broad Institute of MIT and Harvard, Harvard University, Cambridge, MA 02138, USA.
  • Aguado LC; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • Seifert LL; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Center for Clinical and Translational Science, The Rockefeller University, New York, NY 10065, USA.
  • Venkittu S; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • Hong X; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • Shlomai A; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • de Jong YP; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY 10065, USA.
  • Marks DS; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Organismic and Evolutionary Biology, Broad Institute of MIT and Harvard, Harvard University, Cambridge, MA 02138, USA.
  • Rice CM; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. Electronic address: ricec@rockefeller.edu.
  • Schneider WM; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. Electronic address: wschneider@rockefeller.edu.
Cell ; 187(11): 2735-2745.e12, 2024 May 23.
Article in En | MEDLINE | ID: mdl-38723628
ABSTRACT
Hepatitis B virus (HBV) is a small double-stranded DNA virus that chronically infects 296 million people. Over half of its compact genome encodes proteins in two overlapping reading frames, and during evolution, multiple selective pressures can act on shared nucleotides. This study combines an RNA-based HBV cell culture system with deep mutational scanning (DMS) to uncouple cis- and trans-acting sequence requirements in the HBV genome. The results support a leaky ribosome scanning model for polymerase translation, provide a fitness map of the HBV polymerase at single-nucleotide resolution, and identify conserved prolines adjacent to the HBV polymerase termination codon that stall ribosomes. Further experiments indicated that stalled ribosomes tether the nascent polymerase to its template RNA, ensuring cis-preferential RNA packaging and reverse transcription of the HBV genome.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Hepatitis B virus / Reverse Transcription Limits: Humans Language: En Journal: Cell Year: 2024 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Hepatitis B virus / Reverse Transcription Limits: Humans Language: En Journal: Cell Year: 2024 Type: Article Affiliation country: United States