The amino-terminal region of the Vif molecule in human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) contains a conserved SLV/Ix4Yx9Y motif that was first described in 1992, but the importance of this motif for Vif function has not yet been examined. Our characterization of the amino acids surrounding this motif in HIV-1 Vif indicated that the region is critical for APOBEC3 suppression. In particular, amino acids K22, K26, Y30, and Y40 were found to be important for the Vif-induced degradation and suppression of cellular APOBEC3G (A3G). However, mutation of these residues had little effect on the Vif-mediated suppression of A3F, A3C, or A3DE, suggesting that these four residues are not important for Vif assembly with the Cul5 E3 ubiquitin ligase or protein folding in general. The LV portion of the Vif SLV/Ix4 Yx9Y motif was found to be required for optimal suppression of A3F, A3C, or A3DE. Human cytidine deaminase apolipoprotein B mRNA-editing catalytic polypeptide-like 3G (APOBEC3G, here called A3G) and related APOBEC3 proteins are potent inhibitors of diverse viruses and endogenous retroelements (2,9,11,13,18,30,42,47,48,63,72). The Vif protein of human immunodeficiency virus type 1 (HIV-1) and related viruses provides a viral defense against A3G and other APOBEC3 proteins, allowing infection and replication to proceed in host cells. In the absence of the Vif protein, however, A3G is packaged into HIV-1 particles through its interaction with viral Gag molecules (1,7,12,27,41,51,75), with the help of cellular and/or viral genomic RNAs (5,22,61,65,75). Virion-associated A3G induces C-to-U mutations in the newly synthesized viral minusstrand DNA (17,24,31,33,60,71,76) and reduces the accumulation of viral reverse transcripts (3,16,21,28,36,54,70) and the formation of proviral DNA (28, 36) through both deamination-dependent (40, 55) and -independent (4, 43) mechanisms.HIV-1 Vif overcomes the antiviral activity of APOBEC3 by assembling with the components of the cellular cullin 5 (Cul5)-elongin B-elongin C E3 ubiquitin ligase complex (73) to target A3G for proteasomal degradation (10,25,26,35,37,56,59,73). Vif molecules of HIV/simian immunodeficiency virus (SIV) interact with Cul5 using a highly conserved Hx 5 Cx [17][18]
BackgroundAPOBEC3G (A3G) and related cytidine deaminases of the APOBEC3 family of proteins are potent inhibitors of many retroviruses, including HIV-1. Formation of infectious HIV-1 requires the suppression of multiple cytidine deaminases by Vif. HIV-1 Vif suppresses various APOBEC3 proteins through the common mechanism of recruiting the Cullin5-ElonginB-ElonginC E3 ubiquitin ligase to induce target protein polyubiquitination and proteasome-mediated degradation. The domains in Vif and various APOBEC3 proteins required for APOBEC3 recognition and degradation have not been fully characterized.Methods and FindingsIn the present study, we have demonstrated that the regions of APOBEC3F (A3F) that are required for its HIV-1-mediated binding and degradation are distinct from those reported for A3G. We found that the C-terminal cytidine deaminase domain (C-CDD) of A3F alone is sufficient for its interaction with HIV-1 Vif and its Vif-mediated degradation. We also observed that the domains of HIV-1 Vif that are uniquely required for its functional interaction with full-length A3F are also required for the degradation of the C-CDD of A3F; in contrast, those Vif domains that are uniquely required for functional interaction with A3G are not required for the degradation of the C-CDD of A3F. Interestingly, the HIV-1 Vif domains required for the degradation of A3F are also required for the degradation of A3C and A3DE. On the other hand, the Vif domains uniquely required for the degradation of A3G are dispensable for the degradation of cytidine deaminases A3C and A3DE.ConclusionsOur data suggest that distinct regions of A3F and A3G are targeted by HIV-1 Vif molecules. However, HIV-1 Vif suppresses A3F, A3C, and A3DE through similar recognition determinants, which are conserved among Vif molecules from diverse HIV-1 strains. Mapping these determinants may be useful for the design of novel anti-HIV inhibitors.
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