title: Fast track, dynein-dependent nuclear targeting of human immunodeficiency virus Vpr protein; impaired trafficking in a clinical isolate.
abstract: Nuclear import of the accessory protein Vpr is central to infection by human immunodeficiency virus (HIV). We previously identified the Vpr F72L mutation in a HIV-infected, long-term non-progressor, showing that it resulted in reduced Vpr nuclear accumulation and altered cytoplasmic localisation. Here we demonstrate for the first time that the effects of nuclear accumulation of the F72L mutation are due to impairment of microtubule-dependent-enhancement of Vpr nuclear import. We use high resolution imaging approaches including fluorescence recovery after photobleaching and other approaches to document interaction between Vpr and the dynein light chain protein, DYNLT1, and impaired interaction of the F72L mutant with DYNLT1. The results implicate MTs/DYNLT1 as drivers of Vpr nuclear import and HIV infection, with important therapeutic implications.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia.
authors.forename: Leon
authors.initials: L
authors.lastname: Caly
authors.affiliation: Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Vicki T
authors.initials: VT
authors.lastname: Kassouf
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Moseley
authors.affiliation: Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Diefenbach
authors.affiliation: Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Cunningham
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia. Electronic address: david.jans@monash.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Jans
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004398:Dyneins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D013329:Structure-Activity Relationship; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C533376:DYNLT1 protein, human; D054325:vpr Gene Products, Human Immunodeficiency Virus; D004398:Dyneins
keywords: DYNLT1; Dynein; Microtubule; Nuclear import; Viral Protein R; Vpr