Induction of APOBEC3G Ubiquitination and Degradation by an HIV-1 Vif-Cul5-SCF Complex

Abstract

Human immunodeficiency virus-1 (HIV-1) Vif is essential for viral evasion of host antiviral factor CEM15/APOBEC3G. We report that Vif interacts with cellular proteins Cul5, elongins B and C, and Rbx1 to form an Skp1-cullin-F-box (SCF)-like complex. The ability of Vif to suppress antiviral activity of APOBEC3G was specifically dependent on Cul5-SCF function, allowing Vif to interact with APOBEC3G and induce its ubiquitination and degradation. A Vif mutant that interacted with APOBEC3G but not with Cul5-SCF was functionally inactive. The Cul5-SCF was also required for Vif function in distantly related simian immunodeficiency virus mac. These results indicate that the conserved Cul5-SCF pathway used by Vif is a potential target for antiviral development.

APOBEC3F and APOBEC3G mRNA Levels Do Not Correlate with Human Immunodeficiency Virus Type 1 Plasma Viremia or CD4 + T-Cell Count

“…In the absence of the human immunodeficiency virus type 1 (HIV-1) accessory protein Vif, hA3F and hA3G are incorporated into virions and induce G-to-A hypermutations in the viral genome (1,8,12,14,27,29,30). Vif counteracts hA3F and hA3G by preventing their encapsidation within virions and by inducing their proteasomal degradation (4,11,13,16,17,24,25,28). However, higher levels of hA3G expression can overcome the antihost effects of Vif (17), suggesting that regulation of hA3G expression may represent a novel target for antiretroviral therapy and modulation of the progression of HIV-1 infection.…”

Human APOBEC3G-Mediated Editing Can Promote HIV-1 Sequence Diversification and Accelerate Adaptation to Selective Pressure

“…The HIV-1-encoded Vif protein, which serves to induce the proteasomal degradation of A3G through recruitment to the cullin5-elongin BC-rbx2 ubiquitin ligase, efficiently counteracts the potent antiviral phenotype of this enzyme (18,(24)(25)(26)30). It has been suggested that low levels of A3G activity that survive inhibition by Vif may promote infrequent mutations that, rather than preventing virus replication, may provide a source of genetic variation.…”

Cellular defence or viral assist: the dilemma of HDAC6

“…For example, HDAC6 can antagonize HIV-1 infection by inducing autophagic degradation of the viral infection factor (Vif) [109]. Vif recognizes several cellular antiviral proteins, such as APOBEC3G (A3G), promotes their degradation and therefore eludes their restrictive activities against HIV-1 [110,111]. In addition, it was shown that HDAC6 interacts with Vif or A3G and competes for Vif-A3G interaction through its BUZ domain, impairs the incorporation of Vif into nascent virions and finally controls HIV-1 infectiveness (Fig.…”