The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif.
The human protein apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3G (APOBEC3G), also known as CEM-15, mediates a newly described form of innate resistance to retroviral infection by catalyzing the deamination of deoxycytidine to deoxyuridine in viral cDNA replication intermediates. Because DNA deamination takes place after virus entry into target cells, APOBEC3G function is dependent on its association with the viral nucleoprotein complexes that synthesize cDNA and must therefore be incorporated into virions as they assemble in infected cells. Here we show that the HIV-1 virion infectivity factor (Vif) protein protects the virus from APOBEC3G-mediated inactivation by preventing its incorporation into progeny virions, thus allowing the ensuing infection to proceed without DNA deamination. In addition to helping exclude APOBEC3G from nascent virions, Vif also removes APOBEC3G from virus-producing cells by inducing its ubiquitination and subsequent degradation by the proteasome. Our findings indicate that pharmacologic strategies aimed at stabilizing APOBEC3G in HIV-1 infected cells should be explored as potential HIV/AIDS therapeutics.
Sheehy
Ann M
AM
Department of Infectious Diseases, Guy's, King's and St. Thomas' School of Medicine, King's College London, London, SE1 9RT, UK.
Gaddis
Nathan C
NC
Malim
Michael H
MH
D000071480:APOBEC-3G Deaminase; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003564:Cytidine Deaminase; D016346:Gene Products, vif / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D009700:Nucleoside Deaminases; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D019065:Virus Assembly / Q000502:physiology; D054320:vif Gene Products, Human Immunodeficiency Virus
D016346:Gene Products, vif; D009097:Multienzyme Complexes; D011506:Proteins; D012097:Repressor Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase