HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication.
Viral infectivity factor, an accessory protein encoded in the HIV-1 genome, induces G2 cell cycle arrest; however, the biological significance and mechanism(s) remain totally unclear. Here we demonstrate that the TP53 pathway is involved in Vif-mediated G2 cell cycle arrest. Vif enhances the stability and transcriptional activity of TP53 by blocking the MDM2-mediated ubiquitination and nuclear export of TP53. Furthermore, Vif causes G2 cell cycle arrest in a TP53-dependent manner. HXB2 Vif lacks these activities toward TP53 and cannot induce G2 cell cycle arrest. Using mutagenesis, we demonstrate that the critical residues for this function are located in the N-terminal region of Vif. Finally, we construct a mutant NL4-3 virus with an NL4-3/HXB2 chimeric Vif defective for the ability to induce cell cycle arrest and show that the mutant virus replicates less effectively than the wild-type NL4-3 virus in T cells expressing TP53. These data imply that Vif induces G2 cell cycle arrest through functional interaction with the TP53/MDM2 axis and that the G2 cell cycle arrest induced by Vif has a positive effect on HIV-1 replication. This report demonstrates the molecular mechanisms and the biological significance of Vif-mediated G2 cell cycle arrest for HIV-1 infection.
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Taisuke
T
Izumi
Katsuhiro
K
Io
Masashi
M
Matsui
Kotaro
K
Shirakawa
Masanobu
M
Shinohara
Yuya
Y
Nagai
Masahiro
M
Kawahara
Masayuki
M
Kobayashi
Hiroshi
H
Kondoh
Naoko
N
Misawa
Yoshio
Y
Koyanagi
Takashi
T
Uchiyama
Akifumi
A
Takaori-Kondo
D016195:G2 Phase; D045325:HCT116 Cells; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000821:virology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D054320:vif Gene Products, Human Immunodeficiency Virus; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2