effect and positive selection in the HIV-1 vif gene are linked with APOBEC3G/F neutralization
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. Janini3
1Federal 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
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.
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