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HIV-1 subtype C envelope characteristics associated with divergent rates of chronic disease progression.

Archary D, Gordon ML, Green TN, Coovadia HM, Goulder PJ, Ndung'u T - Retrovirology (2010)

Bottom Line: HIV-1 subtype C envelope in particular shows significant differences and unique characteristics compared to its subtype B counterpart.However, intra-patient nucleotide diversity was significantly higher in slow progressors compared to progressors in the C2 (p = 0.0006), V3 (p = 0.01) and C3 (p = 0.005) regions.Similarly, gp41 in the progressors was significantly longer and had fewer PNGs compared to slow progressors (p = 0.02 and p = 0.02 respectively).

View Article: PubMed Central - HTML - PubMed

Affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R, Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.

ABSTRACT

Background: HIV-1 envelope diversity remains a significant challenge for the development of an efficacious vaccine. The evolutionary forces that shape the diversity of envelope are incompletely understood. HIV-1 subtype C envelope in particular shows significant differences and unique characteristics compared to its subtype B counterpart. Here we applied the single genome sequencing strategy of plasma derived virus from a cohort of therapy naïve chronically infected individuals in order to study diversity, divergence patterns and envelope characteristics across the entire HIV-1 subtype C gp160 in 4 slow progressors and 4 progressors over an average of 19.5 months.

Results: Sequence analysis indicated that intra-patient nucleotide diversity within the entire envelope was higher in slow progressors, but did not reach statistical significance (p = 0.07). However, intra-patient nucleotide diversity was significantly higher in slow progressors compared to progressors in the C2 (p = 0.0006), V3 (p = 0.01) and C3 (p = 0.005) regions. Increased amino acid length and fewer potential N-linked glycosylation sites (PNGs) were observed in the V1-V4 in slow progressors compared to progressors (p = 0.009 and p = 0.02 respectively). Similarly, gp41 in the progressors was significantly longer and had fewer PNGs compared to slow progressors (p = 0.02 and p = 0.02 respectively). Positive selection hotspots mapped mainly to V1, C3, V4, C4 and gp41 in slow progressors, whereas hotspots mapped mainly to gp41 in progressors. Signature consensus sequence differences between the groups occurred mainly in gp41.

Conclusions: These data suggest that separate regions of envelope are under differential selective forces, and that envelope evolution differs based on disease course. Differences between slow progressors and progressors may reflect differences in immunological pressure and immune evasion mechanisms. These data also indicate that the pattern of envelope evolution is an important correlate of disease progression in chronic HIV-1 subtype C infection.

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Three dimensional structural illustrations of positions associated with positive negative and neutral selection. Locations were mapped onto a model of gp120 based on the X-ray structure of the gp120 core in complex with sCD4 and 21c Fab (3LQA.pdb) for slow progressors - Figure 4A and for progressors - Figure 4C. V1V2 and V3 loops were drawn onto the core for completeness. In the orientation shown, the cellular and viral membranes would be located above and below the protein respectively. Figure 4B and 4D represent ribbon structures of gp41 for slow progressors and progressors with the MPER region highlighted. Cartoon diagrams showing locations under positive selection, as determined by dN/dS ratios for subtype C sequences. Red indicates strong positive selection (dN/dS >4) as shown above in HXB2 positions 87, 336, 340, 396, 410 and 460 for slow progressors (Figure 4A) and in progressors at positions 350 (Figure 4C) and 607, 612 and 641 in Figure 4D. Blue indicates strongly negatively selected positions (<-3). Purple and purple arrows denote changes in putative functional sites as shown in Figures 4B, 4C and 4D. Spheres indicate signature sequence differences. It should be noted that the gp120 core crystal structures which were modeled on the 3LQA.PDB structure, include amino acid residues from HXB2 position 86-491. The gp41 structure based on 1ENV.pdb includes amino acid residues from HXB2 position 541-662. Therefore all the positively and negatively selected sites are not indicated on the gp120 and gp41 structures.
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Figure 4: Three dimensional structural illustrations of positions associated with positive negative and neutral selection. Locations were mapped onto a model of gp120 based on the X-ray structure of the gp120 core in complex with sCD4 and 21c Fab (3LQA.pdb) for slow progressors - Figure 4A and for progressors - Figure 4C. V1V2 and V3 loops were drawn onto the core for completeness. In the orientation shown, the cellular and viral membranes would be located above and below the protein respectively. Figure 4B and 4D represent ribbon structures of gp41 for slow progressors and progressors with the MPER region highlighted. Cartoon diagrams showing locations under positive selection, as determined by dN/dS ratios for subtype C sequences. Red indicates strong positive selection (dN/dS >4) as shown above in HXB2 positions 87, 336, 340, 396, 410 and 460 for slow progressors (Figure 4A) and in progressors at positions 350 (Figure 4C) and 607, 612 and 641 in Figure 4D. Blue indicates strongly negatively selected positions (<-3). Purple and purple arrows denote changes in putative functional sites as shown in Figures 4B, 4C and 4D. Spheres indicate signature sequence differences. It should be noted that the gp120 core crystal structures which were modeled on the 3LQA.PDB structure, include amino acid residues from HXB2 position 86-491. The gp41 structure based on 1ENV.pdb includes amino acid residues from HXB2 position 541-662. Therefore all the positively and negatively selected sites are not indicated on the gp120 and gp41 structures.

Mentions: Analysis of the entire Env gp160 in the two groups using CODEML and the SLAC option in HYPHY identified 9 common sites under positive selection in slow progressors and 5 sites in progressors. In slow progressors (Figures 4A and 4B), these were at codons 87, 138 and 140 (V1), 336 and 340 (C3), 396 and 410 (V4), 460 (V5) and 832 (gp41). Most of the sites under positive selection in slow progressors were either adjacent to a putative N-linked glycosylation site (codons 87, 138, 336 and 410) or were located at N-linked glycosylation sites (codons 140, 340, 396 and 460). Interestingly, positions 336 and 340 are within the α-2-helix (HXB2 position 335-352); it has been previously reported that changes within this region may confer autologous antibody neutralization resistance [19].


HIV-1 subtype C envelope characteristics associated with divergent rates of chronic disease progression.

Archary D, Gordon ML, Green TN, Coovadia HM, Goulder PJ, Ndung'u T - Retrovirology (2010)

Three dimensional structural illustrations of positions associated with positive negative and neutral selection. Locations were mapped onto a model of gp120 based on the X-ray structure of the gp120 core in complex with sCD4 and 21c Fab (3LQA.pdb) for slow progressors - Figure 4A and for progressors - Figure 4C. V1V2 and V3 loops were drawn onto the core for completeness. In the orientation shown, the cellular and viral membranes would be located above and below the protein respectively. Figure 4B and 4D represent ribbon structures of gp41 for slow progressors and progressors with the MPER region highlighted. Cartoon diagrams showing locations under positive selection, as determined by dN/dS ratios for subtype C sequences. Red indicates strong positive selection (dN/dS >4) as shown above in HXB2 positions 87, 336, 340, 396, 410 and 460 for slow progressors (Figure 4A) and in progressors at positions 350 (Figure 4C) and 607, 612 and 641 in Figure 4D. Blue indicates strongly negatively selected positions (<-3). Purple and purple arrows denote changes in putative functional sites as shown in Figures 4B, 4C and 4D. Spheres indicate signature sequence differences. It should be noted that the gp120 core crystal structures which were modeled on the 3LQA.PDB structure, include amino acid residues from HXB2 position 86-491. The gp41 structure based on 1ENV.pdb includes amino acid residues from HXB2 position 541-662. Therefore all the positively and negatively selected sites are not indicated on the gp120 and gp41 structures.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Three dimensional structural illustrations of positions associated with positive negative and neutral selection. Locations were mapped onto a model of gp120 based on the X-ray structure of the gp120 core in complex with sCD4 and 21c Fab (3LQA.pdb) for slow progressors - Figure 4A and for progressors - Figure 4C. V1V2 and V3 loops were drawn onto the core for completeness. In the orientation shown, the cellular and viral membranes would be located above and below the protein respectively. Figure 4B and 4D represent ribbon structures of gp41 for slow progressors and progressors with the MPER region highlighted. Cartoon diagrams showing locations under positive selection, as determined by dN/dS ratios for subtype C sequences. Red indicates strong positive selection (dN/dS >4) as shown above in HXB2 positions 87, 336, 340, 396, 410 and 460 for slow progressors (Figure 4A) and in progressors at positions 350 (Figure 4C) and 607, 612 and 641 in Figure 4D. Blue indicates strongly negatively selected positions (<-3). Purple and purple arrows denote changes in putative functional sites as shown in Figures 4B, 4C and 4D. Spheres indicate signature sequence differences. It should be noted that the gp120 core crystal structures which were modeled on the 3LQA.PDB structure, include amino acid residues from HXB2 position 86-491. The gp41 structure based on 1ENV.pdb includes amino acid residues from HXB2 position 541-662. Therefore all the positively and negatively selected sites are not indicated on the gp120 and gp41 structures.
Mentions: Analysis of the entire Env gp160 in the two groups using CODEML and the SLAC option in HYPHY identified 9 common sites under positive selection in slow progressors and 5 sites in progressors. In slow progressors (Figures 4A and 4B), these were at codons 87, 138 and 140 (V1), 336 and 340 (C3), 396 and 410 (V4), 460 (V5) and 832 (gp41). Most of the sites under positive selection in slow progressors were either adjacent to a putative N-linked glycosylation site (codons 87, 138, 336 and 410) or were located at N-linked glycosylation sites (codons 140, 340, 396 and 460). Interestingly, positions 336 and 340 are within the α-2-helix (HXB2 position 335-352); it has been previously reported that changes within this region may confer autologous antibody neutralization resistance [19].

Bottom Line: HIV-1 subtype C envelope in particular shows significant differences and unique characteristics compared to its subtype B counterpart.However, intra-patient nucleotide diversity was significantly higher in slow progressors compared to progressors in the C2 (p = 0.0006), V3 (p = 0.01) and C3 (p = 0.005) regions.Similarly, gp41 in the progressors was significantly longer and had fewer PNGs compared to slow progressors (p = 0.02 and p = 0.02 respectively).

View Article: PubMed Central - HTML - PubMed

Affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R, Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.

ABSTRACT

Background: HIV-1 envelope diversity remains a significant challenge for the development of an efficacious vaccine. The evolutionary forces that shape the diversity of envelope are incompletely understood. HIV-1 subtype C envelope in particular shows significant differences and unique characteristics compared to its subtype B counterpart. Here we applied the single genome sequencing strategy of plasma derived virus from a cohort of therapy naïve chronically infected individuals in order to study diversity, divergence patterns and envelope characteristics across the entire HIV-1 subtype C gp160 in 4 slow progressors and 4 progressors over an average of 19.5 months.

Results: Sequence analysis indicated that intra-patient nucleotide diversity within the entire envelope was higher in slow progressors, but did not reach statistical significance (p = 0.07). However, intra-patient nucleotide diversity was significantly higher in slow progressors compared to progressors in the C2 (p = 0.0006), V3 (p = 0.01) and C3 (p = 0.005) regions. Increased amino acid length and fewer potential N-linked glycosylation sites (PNGs) were observed in the V1-V4 in slow progressors compared to progressors (p = 0.009 and p = 0.02 respectively). Similarly, gp41 in the progressors was significantly longer and had fewer PNGs compared to slow progressors (p = 0.02 and p = 0.02 respectively). Positive selection hotspots mapped mainly to V1, C3, V4, C4 and gp41 in slow progressors, whereas hotspots mapped mainly to gp41 in progressors. Signature consensus sequence differences between the groups occurred mainly in gp41.

Conclusions: These data suggest that separate regions of envelope are under differential selective forces, and that envelope evolution differs based on disease course. Differences between slow progressors and progressors may reflect differences in immunological pressure and immune evasion mechanisms. These data also indicate that the pattern of envelope evolution is an important correlate of disease progression in chronic HIV-1 subtype C infection.

Show MeSH
Related in: MedlinePlus