The HIV-1 Vif protein mediates degradation of Vpr and reduces Vpr-induced cell cycle arrest.
Prior work has implicated viral protein R (Vpr) in the arrest of human immunodeficiency virus type 1 (HIV-1)-infected cells in the G2 phase of the cell cycle, associated with increased viral replication and host cell apoptosis. We and others have recently shown that virion infectivity factor (Vif ) also plays a role in the G2 arrest of HIV-1-infected cells. Here, we demonstrate that, paradoxically, at early time points postinfection, Vif expression blocks Vpr-mediated G2 arrest, while deletion of Vif from the HIV-1 genome leads to a marked increase in G2 arrest of infected CD4 T-cells. Consistent with this increased G2 arrest, T-cells infected with Vif-deleted HIV-1 express higher levels of Vpr protein than cells infected with wild-type virus. Further, expression of exogenous Vif inhibits the expression of Vpr, associated with a decrease in G2 arrest of both infected and transfected cells. Treatment with the proteasome inhibitor MG132 increases Vpr protein expression and G2 arrest in wild-type, but not Vif-deleted, NL4-3-infected cells, and in cells cotransfected with Vif and Vpr. In addition, Vpr coimmunoprecipitates with Vif in cotransfected cells in the presence of MG132. This suggests that inhibition of Vpr by Vif is mediated at least in part by proteasomal degradation, similar to Vif-induced degradation of APOBEC3G. Together, these data show that Vif mediates the degradation of Vpr and modulates Vpr-induced G2 arrest in HIV-1-infected T-cells.
Wang
Jiangfang
J
Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Shackelford
Jason M
JM
Selliah
Nithianandan
N
Shivers
Debra K
DK
O'Neill
Eduardo
E
Garcia
J Victor
JV
Muthumani
Karuppiah
K
Weiner
David
D
Yu
Xiao-Fang
XF
Gabuzda
Dana
D
Finkel
Terri H
TH
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016195:G2 Phase; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000254:growth & development / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D014162:Transfection; D014779:Virus Replication; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D054320:vif Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde