The interaction of vpr with uracil DNA glycosylase modulates the human immunodeficiency virus type 1 In vivo mutation rate.
The Vpr protein of human immunodeficiency virus type 1 (HIV-1) influences the in vivo mutation rate of the virus. Since Vpr interacts with a cellular protein implicated in the DNA repair process, uracil DNA glycosylase (UNG), we have explored the contribution of this interaction to the mutation rate of HIV-1. Single-amino-acid variants of Vpr were characterized for their differential UNG-binding properties and used to trans complement vpr null mutant HIV-1. A striking correlation was established between the abilities of Vpr to interact with UNG and to influence the HIV-1 mutation rate. We demonstrate that Vpr incorporation into virus particles is required to influence the in vivo mutation rate and to mediate virion packaging of the nuclear form of UNG. The recruitment of UNG into virions indicates a mechanism for how Vpr can influence reverse transcription accuracy. Our data suggest that distinct mechanisms evolved in primate and nonprimate lentiviruses to reconcile uracil misincorporation into lentiviral DNA.
Mansky
L M
LM
Department of Molecular Virology, Immunology, and Medical Genetics, Center for Retrovirus Research, and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, Ohio 43210, USA. mansky.3@osu.edu
Preveral
S
S
Selig
L
L
Benarous
R
R
Benichou
S
S
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002467:Cell Nucleus / Q000201:enzymology; D045647:DNA Glycosylases; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D005816:Genetic Complementation Test; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D051981:Uracil-DNA Glycosidase; D014771:Virion / Q000378:metabolism; D014779:Virus Replication; D054325:vpr Gene Products, Human Immunodeficiency Virus
D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase