the identification of a small molecule compound that reduces hiv-1 nef-mediated viral infectivity enhancement小分子化合物的识别,减少hiv - 1病毒传染性nef-mediated增强.pdfVIP

The Identification of a Small Molecule Compound That Reduces HIV-1 Nef-Mediated Viral Infectivity Enhancement 1 1 1 1 2 Nopporn Chutiwitoonchai , Masateru Hiyoshi , Philip Mwimanzi , Takamasa Ueno , Akio Adachi , 3 3 4 1 1 Hirotaka Ode , Hironori Sato , Oliver T. Fackler , Seiji Okada , Shinya Suzu * 1 Center for AIDS Research, Kumamoto University, Kumamoto, Japan, 2 Department of Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan, 3 Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan, 4 Department of Infectious Diseases, Virology, University of Heidelberg, Heidelberg, Germany Abstract Nef is a multifunctional HIV-1 protein that accelerates progression to AIDS, and enhances the infectivity of progeny viruses through a mechanism that is not yet understood. Here, we show that the small molecule compound 2c reduces Nef- mediated viral infectivity enhancement. When added to viral producer cells, 2c did not affect the efficiency of viral production itself. However, the infectivity of the viruses produced in the presence of 2c was significantly lower than that of control viruses. Importantly, an inhibitory effect was observed with Nef+ wild-type viruses, but not with viruses produced in the absence of Nef or in the presence of proline-rich PxxP motif-disrupted Nef, both of which displayed significantly reduced intrinsic infectivity. Meanwhile, the overexpression of the SH3 domain of the tyrosine kinase Hck, which binds to a PxxP motif in Nef, also reduced viral infectivity. Importantly, 2c