A single amino acid difference in human APOBEC3H variants determines HIV-1 Vif sensitivity.
Several variants of APOBEC3H (A3H) have been identified in different human populations. Certain variants of this protein are particularly potent inhibitors of retrotransposons and retroviruses, including HIV-1. However, it is not clear whether HIV-1 Vif can recognize and suppress the antiviral activity of A3H variants, as it does with other APOBEC3 proteins. We now report that A3H_Haplotype II (HapII), a potent inhibitor of HIV-1 in the absence of Vif, can indeed be degraded by HIV-1 Vif. Vif-induced degradation of A3H_HapII was blocked by the proteasome inhibitor MG132 and a Cullin5 (Cul5) dominant negative mutant. In addition, Vif mutants that were incapable of assembly with the host E3 ligase complex factors Cul5, ElonginB, and ElonginC were also defective for A3H_HapII suppression. Although we found that Vif hijacks the same E3 ligase to degrade A3H_HapII as it does to inactivate APOBEC3G (A3G) and APOBEC3F (A3F), more Vif motifs were involved in A3H_HapII inactivation than in either A3G or A3F suppression. In contrast to A3H_HapII, A3H_Haplotype I (HapI), which differs in only three amino acids from A3H_HapII, was resistant to HIV-1 Vif-mediated degradation. We also found that residue 121 was critical for determining A3H sensitivity and binding to HIV-1 Vif.
Zhen
Anjie
A
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
Wang
Tao
T
Zhao
Ke
K
Xiong
Yong
Y
Yu
Xiao-Fang
XF
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000619:Aminohydrolases; D001483:Base Sequence; D002460:Cell Line; D043525:Cytosine Deaminase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D016341:Genes, vif; D014644:Genetic Variation; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006239:Haplotypes; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010957:Plasmids / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D011994:Recombinant Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D046988:Proteasome Endopeptidase Complex; C529313:APOBEC3H protein, human; D000619:Aminohydrolases; D043525:Cytosine Deaminase