Abstract

Epistatic effect and positive selection in the HIV-1 vif gene are linked with APOBEC3G/F neutralization activity

E. Leal¹, S. Yabe², H. Kishino², M.C. Bizinoto³, L. de Oliveira Martins⁴, M. Leão de Lima³, E.R. Morais³, R. Sobhie Diaz³, L.M. Janini<sup>3

1</sup>Federal University of Pará, Biotechnology, Belém, Brazil, ²University of Tokyo, Graduate School of Agriculture and Life Sciences, Tokyo, Japan, ³Federal University of São Paulo, Medicine, São Paulo, Brazil, ⁴University of Vigo, Spain, Department of Biochemistry, Genetics and Immunology, Vigo, Spain

Background: The human APOBEC (apolipoprotein B mRNA-editing catalytic polypeptide) gene family includes several members, which have cytidine deaminase activity. Particularly, the genes APOBEC3G (A3G) and APOBEC3F (A3F) present innate immunity able to restrain retroviral infections. Both A3G and A3F induce cytidine deamination (C→U) in the negative strand of HIV-1 during reverse transcription, inducing substitutions of guanosines for adenosines (G→A) in the positive strand. This mechanism is known as hypermutation that may induce appearance of stop codons and consequently loss of reading frames of the viral genes. HIV-1 counteracts A3G activity through ubiquitination of this host protein through the activity of Vif proteins. The vif proteins assemble with viral-specific E3 ubiquitin ligase through its interaction with cellular Cullin5 (Cul5)-ElonginB-ElonginC proteins, inducing ubiquitination of A3G/F and consequent degradation by the proteasomal complex.
Methods: Codon-based models were to explore the evolutionary process in vif gene of 156 sequences of HIV-1 subtype B lineage.
Results: Positively selected sites were concentrated between the WKSLVK and YRHHY regions and within the BC-Box and the Cullin5-Box of vif gene. These regions are involved in the Vif-induced degradation of A3G complexes. Additionally, codons under epistatic effects in the vif gene were detected in the regions DWHLGQGVS, DLADQ and within the BC-Box. Our analysis indicated that positive selection in the vif was not associated with CTL epitope regions (based on epitope maps). Instead, sites under positive selection were more related with A3G/F binding sites in the vif gene. Likewise, epistatic coevolving amino acids in vif were more likely to be found in A3G/F neutralizing sites, including the region ¹⁷¹EDRW¹⁷⁴ recently identified.
Conclusions: Altogether our results suggested that adaptive evolution in the vif gene probably was to optimize A3G/F and cellular proteins (i.e., elongins) binding and recognition, thus indicating the evolutionary plasticity of HIV-1 to adapt the host antiviral genes.