MBE Advance Access originally published online on October 5, 2007
Molecular Biology and Evolution 2007 24(12):2787-2801; doi:10.1093/molbev/msm213
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Research Articles |
A Study of the Coevolutionary Patterns Operating within the env Gene of the HIV-1 Group M Subtypes
,1
* Molecular Evolution and Bioinformatics Laboratory, Department of Biology, National University of Ireland, Maynooth, Ireland
Evolutionary Genetics and Bioinformatics Laboratory, Department of Genetics, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, 2, Ireland 4
Molecular Evolution and Systematics Laboratory, Martin Ryan Institute, National University of Ireland, Galway, Ireland
E-mail: faresm{at}tcd.ie.
Accepted for publication September 26, 2007.
The env gene of human immunodeficiency virus (HIV) is a functionally important gene responsible for the production of protein products (gp120 and gp41) involved in host cell recognition, binding, and entry. This occurs through a complex and, as yet, not fully understood process of protein–protein interaction and within and between protein functional communication. Exposure on the surface of active HIV virions means the gp120–gp41 complexes are subjected to intense immune system pressure and have, therefore, evolved mechanisms to avoid neutralization. Using protein-coding sequences representing all the HIV type-1 (HIV-1) group M subtypes, we have identified amino acids within the env gene whose evolution is inextricably linked over the entire HIV-1 group M epidemic. We identified 848 pairs of coevolving residues (involving 263 out of 764 amino acid sites), which represent 0.29% of all possible pairs. Of the coevolving pairs, 68% were significantly correlated by hydrophobicity, molecular weight, or both hydrophobicity and molecular weight. Subsequent grouping of coevolving pairs resulted in the identification of 290 groups of amino acid residues, with the size of these groups ranging from 2 to 10 amino acid residues. Many of these dependencies are correlated by function including CD4 binding, coreceptor binding, glycosylation, and protein–protein interaction. This analysis provides important information regarding the functional dependencies observed within all the HIV-1 group M subtypes and may assist in the identification of functional protein domains and therapeutic targets within the HIV-1 env gene.
Key Words: coevolution • HIV-1 • env • M subtypes
1 S.A.A.T. and D.C.T. contributed equally to this study.