Kessl Jacques J, Kutluay Sebla B, Townsend Dana, Rebensburg Stephanie, Slaughter Alison, Larue Ross C, Shkriabai Nikoloz, Bakouche Nordine, Fuchs James R, Bieniasz Paul D, Kvaratskhelia Mamuka
Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
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.
Cell. 2016 Aug 25;166(5):1257-1268.e12. doi: 10.1016/j.cell.2016.07.044.
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.
虽然HIV-1整合酶（IN）在将病毒cDNA整合到人类染色体中的关键作用已得到证实，但对IN突变体和变构IN抑制剂（ALLINIs）的研究表明，IN也可影响病毒颗粒成熟。然而，IN如何促进病毒体形态发生仍不清楚。在此，我们证明IN直接结合病毒体中的病毒RNA基因组。这些相互作用具有特异性，因为IN对特定的病毒RNA结构元件表现出明显的偏好。我们表明，选择性损害其与病毒RNA结合的IN替代导致偏心、无感染性的病毒体，而不影响核衣壳-RNA相互作用。同样，ALLINIs损害野生型病毒体中IN与病毒RNA的结合，但不影响逃逸突变体病毒。这些结果揭示了IN在病毒体形态发生过程中与病毒RNA基因组结合的意外生物学作用，并阐明了ALLINIs的作用模式。
