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. 2000 May;74(9):4335-50.
doi: 10.1128/jvi.74.9.4335-4350.2000.

Reevaluation of amino acid variability of the human immunodeficiency virus type 1 gp120 envelope glycoprotein and prediction of new discontinuous epitopes

Y Yamaguchi-Kabata  1 , T Gojobori
Affiliations

Reevaluation of amino acid variability of the human immunodeficiency virus type 1 gp120 envelope glycoprotein and prediction of new discontinuous epitopes

Y Yamaguchi-Kabata et al. J Virol. 2000 May.

Abstract

To elucidate the evolutionary mechanisms of the human immunodeficiency virus type 1 gp120 envelope glycoprotein at the single-site level, the degree of amino acid variation and the numbers of synonymous and nonsynonymous substitutions were examined in 186 nucleotide sequences for gp120 (subtype B). Analyses of amino acid variabilities showed that the level of variability was very different from site to site in both conserved (C1 to C5) and variable (V1 to V5) regions previously assigned. To examine the relative importance of positive and negative selection for each amino acid position, the numbers of synonymous and nonsynonymous substitutions that occurred at each codon position were estimated by taking phylogenetic relationships into account. Among the 414 codon positions examined, we identified 33 positions where nonsynonymous substitutions were significantly predominant. These positions where positive selection may be operating, which we call putative positive selection (PS) sites, were found not only in the variable loops but also in the conserved regions (C1 to C4). In particular, we found seven PS sites at the surface positions of the alpha-helix (positions 335 to 347 in the C3 region) in the opposite face for CD4 binding. Furthermore, two PS sites in the C2 region and four PS sites in the C4 region were detected in the same face of the protein. The PS sites found in the C2, C3, and C4 regions were separated in the amino acid sequence but close together in the three-dimensional structure. This observation suggests the existence of discontinuous epitopes in the protein's surface including this alpha-helix, although the antigenicity of this area has not been reported yet.

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Figures

FIG. 1
FIG. 1
Amino acid variabilities of HIV-1 gp120 at the single-amino-acid-site level by three different measures. At the top of each section is shown the amino acid sequence of HXB2. The locations of the conserved (C1 to C5) and variable (V1 to V5) regions are shown. Lowercase letters represent amino acid sites that were not analyzed in this study. Below the sequence are shown amino acid variabilities for sites within that sequence as estimated by three measures, acceptability (number of different amino acids), changeability (number of substitutions), and diversity.
FIG. 1
FIG. 1
Amino acid variabilities of HIV-1 gp120 at the single-amino-acid-site level by three different measures. At the top of each section is shown the amino acid sequence of HXB2. The locations of the conserved (C1 to C5) and variable (V1 to V5) regions are shown. Lowercase letters represent amino acid sites that were not analyzed in this study. Below the sequence are shown amino acid variabilities for sites within that sequence as estimated by three measures, acceptability (number of different amino acids), changeability (number of substitutions), and diversity.
FIG. 1
FIG. 1
Amino acid variabilities of HIV-1 gp120 at the single-amino-acid-site level by three different measures. At the top of each section is shown the amino acid sequence of HXB2. The locations of the conserved (C1 to C5) and variable (V1 to V5) regions are shown. Lowercase letters represent amino acid sites that were not analyzed in this study. Below the sequence are shown amino acid variabilities for sites within that sequence as estimated by three measures, acceptability (number of different amino acids), changeability (number of substitutions), and diversity.
FIG. 1
FIG. 1
Amino acid variabilities of HIV-1 gp120 at the single-amino-acid-site level by three different measures. At the top of each section is shown the amino acid sequence of HXB2. The locations of the conserved (C1 to C5) and variable (V1 to V5) regions are shown. Lowercase letters represent amino acid sites that were not analyzed in this study. Below the sequence are shown amino acid variabilities for sites within that sequence as estimated by three measures, acceptability (number of different amino acids), changeability (number of substitutions), and diversity.
FIG. 2
FIG. 2
PS sites and NS sites in HIV-1 gp120. PS sites (red +) and NS sites (blue −) are shown in the amino acid sequence of strain HXBc2. Amino acid positions for CD4 binding (33) are indicated by orange asterisks. Amino acid positions where substitutions are critical for CCR5 binding (46) are indicated by green asterisks. Amino acid positions for disulfide bonding (36) are indicated by purple ^. Lowercase letters represent amino acid sites that were not tested. Approximate locations for the outer domain, the inner domain, and the bridging sheet (33) are shown by pink, light blue, and yellow-green bars, respectively.
FIG. 3
FIG. 3
Locations of PS sites and NS sites of HIV-1 gp120 in the three-dimensional structure. Molecular graphics were produced using Rasmol (50). The locations of PS sites (red) and NS sites (blue) are shown. Green, amino acid sites where no significant difference was detected. Gray, not tested (A) All amino acid sites of gp120 are shown. Circled single-letter amino acid codes represent positions where structures were not solved (33). (B through D) Locations of PS sites and NS sites in the gp120 core shown in four different views. Four views of the molecule are given. The PS sites are labeled. (B) Face for CD4 binding. (C) Face opposite that of CD4 binding. (D) Outer domain. (E) Inner domain.
FIG. 3
FIG. 3
Locations of PS sites and NS sites of HIV-1 gp120 in the three-dimensional structure. Molecular graphics were produced using Rasmol (50). The locations of PS sites (red) and NS sites (blue) are shown. Green, amino acid sites where no significant difference was detected. Gray, not tested (A) All amino acid sites of gp120 are shown. Circled single-letter amino acid codes represent positions where structures were not solved (33). (B through D) Locations of PS sites and NS sites in the gp120 core shown in four different views. Four views of the molecule are given. The PS sites are labeled. (B) Face for CD4 binding. (C) Face opposite that of CD4 binding. (D) Outer domain. (E) Inner domain.
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