Study of anti-APOBEC3G activities of HIV-1 Vif proteins among different subtypes

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Antiretroviral cytidine deaminase APOBEC3G, which is abundantly expressed in peripheral blood lymphocytes and macrophages, strongly protects these cells against HIV-I infection. The Vif protein of HIV-1 overcomes this antiviral effect by inducing proteasome-mediated degradation of APOBEC3G, and is a key for maintaining viral infectivity. The vif gene, which is 579-bp long, displays high genetic diversity among HIV-I subtypes and it is therefore intriguing to address whether Vif proteins derived from different subtypes might be differ in the viral defense activity against APOBEC3G. To test this, we created expression plasmids encoding Vif proteins derived from subtypes A, B, C, CRF01_AE, and CRF02_AG clinical isolates and compared their anti-APOBEC3G activities. Viruses, produced from cells in the presence of APOBEC3G and Vif proteins of different subtypes, showed differential viral infectivities, that is, subtype C-derived Vif proteins showed exclusively high anti-APOBEC3G activities, compared with any. other subtype-derived Vif proteins, and this was found to be because of the different levels of proteasomal APOBEC3G degradation by Vif, depending on subtypes. To determine which portion of subtype C-Vif protein would be responsible for the robust anit-APOBEC3G activities, we created chimeric Vif constructs between subtypes B and C, and further pursued the responsible amino acid (s) by generating point mutants of Vif plasmids. As a result, we identified two amino acids at N-terminus responsible for subtype C-Vif-specific anti-APOBEC3G activity. Intriguingly, one of these amino acids is contained in the conserved sequence which is proposed to be involved in the interaction with APOBEC3G, suggesting that subtype C-vif might be able to bind APOBEC3G more efficiently than do Vif proteins of other subtypes. These results imply that biological differences of Vif proteins among subtypes might have an impact on viral transmissibility.