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An integrated map of HIV genome-wide variation from a population perspective.

Li G, Piampongsant S, Faria NR, Voet A, Pineda-Peña AC, Khouri R, Lemey P, Vandamme AM, Theys K - Retrovirology (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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An integrated map of HIV-1 genomic diversity and protein structures. All 15 HIV-1 proteins are mapped in the circle with 8 layers, showing the schematic view of HIV-1 peptide inhibitors (layer 1), protein secondary structures (layer 2, dark blue: helix structures, light blue: beta-strand structures, white: random-coil structures), protein disorder scores (layer 3), amino acid diversity at individual positions (layer 4), human CD4/CD8/antibody epitope regions (layer 5, three sub-layers from inside to outside represent CD8+ T cell, CD4+ T cell and antibody epitope regions), HXB2 reference indices (layer 6), peptide-inhibitor-derived regions (layer 7) and the protein structures are colored according to the diversity of amino acid positions (layer 8, low: 0%, high: ≥30%). Three major genes (gag, pol, env) are annotated in the center. Structures of multimeric HIV-1 proteins are shown outside the circle and different protein units are colored separately. The list of PDB data is available in Additional file 2: Table S5. Visualization software: Circos V0.64 (http://circos.ca/).
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Fig6: An integrated map of HIV-1 genomic diversity and protein structures. All 15 HIV-1 proteins are mapped in the circle with 8 layers, showing the schematic view of HIV-1 peptide inhibitors (layer 1), protein secondary structures (layer 2, dark blue: helix structures, light blue: beta-strand structures, white: random-coil structures), protein disorder scores (layer 3), amino acid diversity at individual positions (layer 4), human CD4/CD8/antibody epitope regions (layer 5, three sub-layers from inside to outside represent CD8+ T cell, CD4+ T cell and antibody epitope regions), HXB2 reference indices (layer 6), peptide-inhibitor-derived regions (layer 7) and the protein structures are colored according to the diversity of amino acid positions (layer 8, low: 0%, high: ≥30%). Three major genes (gag, pol, env) are annotated in the center. Structures of multimeric HIV-1 proteins are shown outside the circle and different protein units are colored separately. The list of PDB data is available in Additional file 2: Table S5. Visualization software: Circos V0.64 (http://circos.ca/).

Mentions: Integrated findings from our analyses on HIV-1 genomic diversity, HIV-derived peptide inhibitors and protein structures are visualized in Figure 6. The HIV genomic sequence datasets and our toolbox developed for data visualization, genomic diversity analysis and HIV genomic alignments are freely available in Additional file 3.Figure 6


An integrated map of HIV genome-wide variation from a population perspective.

Li G, Piampongsant S, Faria NR, Voet A, Pineda-Peña AC, Khouri R, Lemey P, Vandamme AM, Theys K - Retrovirology (2015)

An integrated map of HIV-1 genomic diversity and protein structures. All 15 HIV-1 proteins are mapped in the circle with 8 layers, showing the schematic view of HIV-1 peptide inhibitors (layer 1), protein secondary structures (layer 2, dark blue: helix structures, light blue: beta-strand structures, white: random-coil structures), protein disorder scores (layer 3), amino acid diversity at individual positions (layer 4), human CD4/CD8/antibody epitope regions (layer 5, three sub-layers from inside to outside represent CD8+ T cell, CD4+ T cell and antibody epitope regions), HXB2 reference indices (layer 6), peptide-inhibitor-derived regions (layer 7) and the protein structures are colored according to the diversity of amino acid positions (layer 8, low: 0%, high: ≥30%). Three major genes (gag, pol, env) are annotated in the center. Structures of multimeric HIV-1 proteins are shown outside the circle and different protein units are colored separately. The list of PDB data is available in Additional file 2: Table S5. Visualization software: Circos V0.64 (http://circos.ca/).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4358901&req=5

Fig6: An integrated map of HIV-1 genomic diversity and protein structures. All 15 HIV-1 proteins are mapped in the circle with 8 layers, showing the schematic view of HIV-1 peptide inhibitors (layer 1), protein secondary structures (layer 2, dark blue: helix structures, light blue: beta-strand structures, white: random-coil structures), protein disorder scores (layer 3), amino acid diversity at individual positions (layer 4), human CD4/CD8/antibody epitope regions (layer 5, three sub-layers from inside to outside represent CD8+ T cell, CD4+ T cell and antibody epitope regions), HXB2 reference indices (layer 6), peptide-inhibitor-derived regions (layer 7) and the protein structures are colored according to the diversity of amino acid positions (layer 8, low: 0%, high: ≥30%). Three major genes (gag, pol, env) are annotated in the center. Structures of multimeric HIV-1 proteins are shown outside the circle and different protein units are colored separately. The list of PDB data is available in Additional file 2: Table S5. Visualization software: Circos V0.64 (http://circos.ca/).
Mentions: Integrated findings from our analyses on HIV-1 genomic diversity, HIV-derived peptide inhibitors and protein structures are visualized in Figure 6. The HIV genomic sequence datasets and our toolbox developed for data visualization, genomic diversity analysis and HIV genomic alignments are freely available in Additional file 3.Figure 6

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

Show MeSH