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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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Nucleotide and amino acid composition of HIV genomes and 3D mapping of HIV-human protein interactions. (A) Nucleotide composition for HIV-1 and HIV-2. X-axis represents the HIV groups, subtypes and CRFs. Y-axis shows the average proportions of nucleotides (A, T, C, G) using the HIV genomic sequence datasets (one sequence per patient, Table 1). (B) Amino acid composition for HIV-1 and HIV-2. X-axis represents HIV groups, subtypes and CRFs. Y-axis shows the average proportions of amino acids using the HIV protein sequence datasets (one sequence per patient, Table 1). (C) Distribution plots of amino acid genetic diversity for 15 HIV-1 subtype B proteins. Each subplot demonstrates a viral protein. X- and y-axes indicate the amino acid diversity and the proportions of amino acid diversity, respectively. Red lines inside the distribution plots indicate the mean values of amino acid diversity at individual proteins. (D) Top and side views of 3D HIV-human protein interaction networks. HIV-1 proteins with protein names annotated are indicated by green spheres. Human proteins that interact with only one HIV-1 protein are indicated by blue spheres in the outer circle (one human protein one sphere). Human proteins that interact with more than one HIV-1 protein are indicated by purple spheres above the plane of HIV-1 proteins. The height of the layers above the plane indicates the number of HIV proteins that a human protein interacts with. Below, human proteins are clustered if they interact with a set of more than one HIV-1 protein. Abbreviation names have been described in the abbreviation list. Visualization software: Geomi V2.0(http://sydney.edu.au/engineering/it/~visual/geomi2/).
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Fig3: Nucleotide and amino acid composition of HIV genomes and 3D mapping of HIV-human protein interactions. (A) Nucleotide composition for HIV-1 and HIV-2. X-axis represents the HIV groups, subtypes and CRFs. Y-axis shows the average proportions of nucleotides (A, T, C, G) using the HIV genomic sequence datasets (one sequence per patient, Table 1). (B) Amino acid composition for HIV-1 and HIV-2. X-axis represents HIV groups, subtypes and CRFs. Y-axis shows the average proportions of amino acids using the HIV protein sequence datasets (one sequence per patient, Table 1). (C) Distribution plots of amino acid genetic diversity for 15 HIV-1 subtype B proteins. Each subplot demonstrates a viral protein. X- and y-axes indicate the amino acid diversity and the proportions of amino acid diversity, respectively. Red lines inside the distribution plots indicate the mean values of amino acid diversity at individual proteins. (D) Top and side views of 3D HIV-human protein interaction networks. HIV-1 proteins with protein names annotated are indicated by green spheres. Human proteins that interact with only one HIV-1 protein are indicated by blue spheres in the outer circle (one human protein one sphere). Human proteins that interact with more than one HIV-1 protein are indicated by purple spheres above the plane of HIV-1 proteins. The height of the layers above the plane indicates the number of HIV proteins that a human protein interacts with. Below, human proteins are clustered if they interact with a set of more than one HIV-1 protein. Abbreviation names have been described in the abbreviation list. Visualization software: Geomi V2.0(http://sydney.edu.au/engineering/it/~visual/geomi2/).

Mentions: Among all HIV proteins, Integrase was the most conserved protein (mean ± deviation: 4.5 ± 1.1%), while GP120 varied the most (21.3 ± 2.5%) (Table 2). Pairwise comparisons of genetic diversity between subtype B and the other clades identified conserved regions in the Capsid, Nucleocapsid, Protease, RT, Integrase, Vpr and the N terminus of GP41 (Figure 2C). Despite the different degrees of sequence diversity along the full-length genome, the nucleotide and amino acid compositions were comparable across the 16 group and subtype genomes (Figure 3A, 3B).Table 2


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)

Nucleotide and amino acid composition of HIV genomes and 3D mapping of HIV-human protein interactions. (A) Nucleotide composition for HIV-1 and HIV-2. X-axis represents the HIV groups, subtypes and CRFs. Y-axis shows the average proportions of nucleotides (A, T, C, G) using the HIV genomic sequence datasets (one sequence per patient, Table 1). (B) Amino acid composition for HIV-1 and HIV-2. X-axis represents HIV groups, subtypes and CRFs. Y-axis shows the average proportions of amino acids using the HIV protein sequence datasets (one sequence per patient, Table 1). (C) Distribution plots of amino acid genetic diversity for 15 HIV-1 subtype B proteins. Each subplot demonstrates a viral protein. X- and y-axes indicate the amino acid diversity and the proportions of amino acid diversity, respectively. Red lines inside the distribution plots indicate the mean values of amino acid diversity at individual proteins. (D) Top and side views of 3D HIV-human protein interaction networks. HIV-1 proteins with protein names annotated are indicated by green spheres. Human proteins that interact with only one HIV-1 protein are indicated by blue spheres in the outer circle (one human protein one sphere). Human proteins that interact with more than one HIV-1 protein are indicated by purple spheres above the plane of HIV-1 proteins. The height of the layers above the plane indicates the number of HIV proteins that a human protein interacts with. Below, human proteins are clustered if they interact with a set of more than one HIV-1 protein. Abbreviation names have been described in the abbreviation list. Visualization software: Geomi V2.0(http://sydney.edu.au/engineering/it/~visual/geomi2/).
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Fig3: Nucleotide and amino acid composition of HIV genomes and 3D mapping of HIV-human protein interactions. (A) Nucleotide composition for HIV-1 and HIV-2. X-axis represents the HIV groups, subtypes and CRFs. Y-axis shows the average proportions of nucleotides (A, T, C, G) using the HIV genomic sequence datasets (one sequence per patient, Table 1). (B) Amino acid composition for HIV-1 and HIV-2. X-axis represents HIV groups, subtypes and CRFs. Y-axis shows the average proportions of amino acids using the HIV protein sequence datasets (one sequence per patient, Table 1). (C) Distribution plots of amino acid genetic diversity for 15 HIV-1 subtype B proteins. Each subplot demonstrates a viral protein. X- and y-axes indicate the amino acid diversity and the proportions of amino acid diversity, respectively. Red lines inside the distribution plots indicate the mean values of amino acid diversity at individual proteins. (D) Top and side views of 3D HIV-human protein interaction networks. HIV-1 proteins with protein names annotated are indicated by green spheres. Human proteins that interact with only one HIV-1 protein are indicated by blue spheres in the outer circle (one human protein one sphere). Human proteins that interact with more than one HIV-1 protein are indicated by purple spheres above the plane of HIV-1 proteins. The height of the layers above the plane indicates the number of HIV proteins that a human protein interacts with. Below, human proteins are clustered if they interact with a set of more than one HIV-1 protein. Abbreviation names have been described in the abbreviation list. Visualization software: Geomi V2.0(http://sydney.edu.au/engineering/it/~visual/geomi2/).
Mentions: Among all HIV proteins, Integrase was the most conserved protein (mean ± deviation: 4.5 ± 1.1%), while GP120 varied the most (21.3 ± 2.5%) (Table 2). Pairwise comparisons of genetic diversity between subtype B and the other clades identified conserved regions in the Capsid, Nucleocapsid, Protease, RT, Integrase, Vpr and the N terminus of GP41 (Figure 2C). Despite the different degrees of sequence diversity along the full-length genome, the nucleotide and amino acid compositions were comparable across the 16 group and subtype genomes (Figure 3A, 3B).Table 2

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
Related in: MedlinePlus