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Acceso Abierto
An integrated map of HIV genome-wide variation from a population perspective
Título de la revista
Autores
Li, Guangdi
Piampongsant, Supinya
Faria, Nuno Rodrigues
Voet, Arnout
Pineda-Peña, Andrea-Clemencia
Khouri, Ricardo
Lemey, Philippe
Vandamme, Anne-Mieke
Theys, Kristof
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Fecha
2015
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Editor
BioMed Central Ltd.
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Resumen
Abstract
Background: The HIV pandemic is characterized by extensive genetic variability, which has challenged the development of HIV drugs and vaccines. Although HIV genomes have been classified into different types, groups, subtypes and recombinants, a comprehensive study that maps HIV genome-wide diversity at the population level is still lacking to date. This study aims to characterize HIV genomic diversity in large-scale sequence populations, and to identify driving factors that shape HIV genome diversity. Results: A total of 2996 full-length genomic sequences from 1705 patients infected with 16 major HIV groups, subtypes and circulating recombinant forms (CRFs) were analyzed along with structural, immunological and peptide inhibitor information. Average nucleotide diversity of HIV genomes was almost 50% between HIV-1 and HIV-2 types, 37.5% between HIV-1 groups, 14.7% between HIV-1 subtypes, 8.2% within individual HIV-1 subtypes and less than 1% within single patients. Along the HIV genome, diversity patterns and compositions of nucleotides and amino acids were highly similar across different groups, subtypes and CRFs. Current HIV-derived peptide inhibitors were predominantly derived from conserved, solvent accessible and intrinsically ordered structures in the HIV-1 subtype B genome. We identified these conserved regions in Capsid, Nucleocapsid, Protease, Integrase, Reverse transcriptase, Vpr and the GP41 N terminus as potential drug targets. In the analysis of factors that impact HIV-1 genomic diversity, we focused on protein multimerization, immunological constraints and HIV-human protein interactions. We found that amino acid diversity in monomeric proteins was higher than in multimeric proteins, and diversified positions were preferably located within human CD4 T cell and antibody epitopes. Moreover, intrinsic disorder regions in HIV-1 proteins coincided with high levels of amino acid diversity, facilitating a large number of interactions between HIV-1 and human proteins. Conclusions: This first large-scale analysis provided a detailed mapping of HIV genomic diversity and highlighted drug-target regions conserved across different groups, subtypes and CRFs. Our findings suggest that, in addition to the impact of protein multimerization and immune selective pressure on HIV-1 diversity, HIV-human protein interactions are facilitated by high variability within intrinsically disordered structures. © 2015 Li et al.; licensee BioMed Central.
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Keywords
Epitope , dna , Integrase , Nucleocapsid protein , Proteinase , Rna directed dna polymerase , Vpr protein , Article , Cd4 lymphocyte count , Cladistics , Gene mapping , Genetic analysis , Genetic association , Genetic conservation , Genetic variability , Human immunodeficiency virus , Human immunodeficiency virus 1 , Human immunodeficiency virus 2 , Nonhuman , Open reading frame , Phylogeny , Promoter region , Protein multimerization , Sequence analysis , Viral genetics , Virus particle , Dna sequence , Genetic variability , Genetics , Human , Human immunodeficiency virus infection , Virology , Virus genome , Human immunodeficiency virus 1 , Human immunodeficiency virus 2 , Miridae , Genetic variation , Genome , Hiv infections , Hiv-1 , Humans , Sequence analysis , Conservation , Genomic diversity , Hiv genome , Hiv inter- and inter-clade genetic diversity , Hiv phylogenetic tree , Hiv-human protein interaction , Peptide inhibitor , Protein intrinsic disorder , Protein multimerization , Selective pressure
