title: HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis.
abstract: While an essential role of HIV-1 integrase (IN) for integration of viral cDNA into human chromosome is established, studies with IN mutants and allosteric IN inhibitors (ALLINIs) have suggested that IN can also influence viral particle maturation. However, it has remained enigmatic as to how IN contributes to virion morphogenesis. Here, we demonstrate that IN directly binds the viral RNA genome in virions. These interactions have specificity, as IN exhibits distinct preference for select viral RNA structural elements. We show that IN substitutions that selectively impair its binding to viral RNA result in eccentric, non-infectious virions without affecting nucleocapsid-RNA interactions. Likewise, ALLINIs impair IN binding to viral RNA in virions of wild-type, but not escape mutant, virus. These results reveal an unexpected biological role of IN binding to the viral RNA genome during virion morphogenesis and elucidate the mode of action of ALLINIs.
authors: Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors: Jacques J
authors: JJ
authors: Kessl
authors: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Laboratory of Retrovirology, Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016, USA.
authors: Sebla B
authors: SB
authors: Kutluay
authors: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Dana
authors: D
authors: Townsend
authors: Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors: Stephanie
authors: S
authors: Rebensburg
authors: Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors: Alison
authors: A
authors: Slaughter
authors: Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors: Ross C
authors: RC
authors: Larue
authors: Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors: Nikoloz
authors: N
authors: Shkriabai
authors: Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors: Nordine
authors: N
authors: Bakouche
authors: College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors: James R
authors: JR
authors: Fuchs
authors: Laboratory of Retrovirology, Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016, USA; Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016, USA.
authors: Paul D
authors: PD
authors: Bieniasz
authors: Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA. Electronic address: kvaratskhelia.1@osu.edu.
authors: Mamuka
authors: M
authors: Kvaratskhelia
mesh_terms: D016679:Genome, Viral; D057809:HEK293 Cells; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D006801:Humans; D009024:Morphogenesis; D019251:Nucleocapsid / Q000187:drug effects; D011485:Protein Binding; D012367:RNA, Viral / Q000378:metabolism*; D014771:Virion / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D016662:Virus Integration / Q000187:drug effects
chemical_list: D019428:HIV Integrase Inhibitors; D012367:RNA, Viral; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1