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The role of the humoral immune response in the molecular evolution of the envelope C2, V3 and C3 regions in chronically HIV-2 infected patients.

Borrego P, Marcelino JM, Rocha C, Doroana M, Antunes F, Maltez F, Gomes P, Novo C, Barroso H, Taveira N - Retrovirology (2008)

Bottom Line: Variation of the C2V3C3-specific IgA response was inversely associated with variation in the number of N-glycosylation sites.C2V3C3-specific IgG antibodies are effective at reducing viral population size limiting the number of virus escape mutants.Our results provide new insights into the biology of HIV-2 and its relation with the human host and may have important implications for vaccine design.

View Article: PubMed Central - HTML - PubMed

Affiliation: URIA-CPM, Faculdade de Farmácia de Lisboa, Avenida das Forças Armadas, 1649-019 Lisbon, Portugal. pborrego@ff.ul.pt

ABSTRACT

Background: This study was designed to investigate, for the first time, the short-term molecular evolution of the HIV-2 C2, V3 and C3 envelope regions and its association with the immune response. Clonal sequences of the env C2V3C3 region were obtained from a cohort of eighteen HIV-2 chronically infected patients followed prospectively during 2-4 years. Genetic diversity, divergence, positive selection and glycosylation in the C2V3C3 region were analysed as a function of the number of CD4+ T cells and the anti-C2V3C3 IgG and IgA antibody reactivity

Results: The mean intra-host nucleotide diversity was 2.1% (SD, 1.1%), increasing along the course of infection in most patients. Diversity at the amino acid level was significantly lower for the V3 region and higher for the C2 region. The average divergence rate was 0.014 substitutions/site/year, which is similar to that reported in chronic HIV-1 infection. The number and position of positively selected sites was highly variable, except for codons 267 and 270 in C2 that were under strong and persistent positive selection in most patients. N-glycosylation sites located in C2 and V3 were conserved in all patients along the course of infection. Intra-host variation of C2V3C3-specific IgG response over time was inversely associated with the variation in nucleotide and amino acid diversity of the C2V3C3 region. Variation of the C2V3C3-specific IgA response was inversely associated with variation in the number of N-glycosylation sites.

Conclusion: The evolutionary dynamics of HIV-2 envelope during chronic aviremic infection is similar to HIV-1 implying that the virus should be actively replicating in cellular compartments. Convergent evolution of N-glycosylation in C2 and V3, and the limited diversification of V3, indicates that there are important functional constraints to the potential diversity of the HIV-2 envelope. C2V3C3-specific IgG antibodies are effective at reducing viral population size limiting the number of virus escape mutants. The C3 region seems to be a target for IgA antibodies and increasing N-linked glycosylation may prevent HIV-2 envelope recognition by these antibodies. Our results provide new insights into the biology of HIV-2 and its relation with the human host and may have important implications for vaccine design.

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Maximum-likelihood phylogenetic analysis. The phylogenetic tree was constructed with reference sequences from HIV-2 groups A, B and G, under the TVM+G+I evolutionary model, using the NNI heuristic search strategy and 1000 bootstrap replications. The triangles represent the compressed subtrees containing clonal sequences obtained from all samples collected for each patient. The length of the triangle represents the intra-patient nucleotide diversity and its thickness is proportional to the number of sequences. The bootstrap values supporting the internal branches are shown. The scale bar represents evolutionary distances in substitutions per site. The inset contains the subtrees of patient PTHCC1 (A), PTHCC20 (B) and PTHCC5 (C) (Yellow circle – 2003; green circle – 2004; blue circle – 2005).
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Figure 1: Maximum-likelihood phylogenetic analysis. The phylogenetic tree was constructed with reference sequences from HIV-2 groups A, B and G, under the TVM+G+I evolutionary model, using the NNI heuristic search strategy and 1000 bootstrap replications. The triangles represent the compressed subtrees containing clonal sequences obtained from all samples collected for each patient. The length of the triangle represents the intra-patient nucleotide diversity and its thickness is proportional to the number of sequences. The bootstrap values supporting the internal branches are shown. The scale bar represents evolutionary distances in substitutions per site. The inset contains the subtrees of patient PTHCC1 (A), PTHCC20 (B) and PTHCC5 (C) (Yellow circle – 2003; green circle – 2004; blue circle – 2005).

Mentions: To investigate the molecular evolution of the HIV-2 env gene we have amplified, cloned and sequenced the env gene fragment coding for the C2, V3 and C3 regions using yearly samples collected from 18 patients followed prospectively for 2–4 years. A total of 431 clonal sequences were obtained from 18 patients (average of 13 sequences per patient per sampling year). Phylogenetic analysis showed that all sequences clustered together within HIV-2 group A and that each patient sequences formed monophyletic sub-clusters with high bootstrap supporting values (Figure 1). Phylogenetic analysis also showed that with the exceptions of patients PTHCC1, PTHCC5 and PTHCC20, sequences from most patients were not segregated according to sampling years, a clear indication that there were no major shifts in virus population structure from one year to the other.


The role of the humoral immune response in the molecular evolution of the envelope C2, V3 and C3 regions in chronically HIV-2 infected patients.

Borrego P, Marcelino JM, Rocha C, Doroana M, Antunes F, Maltez F, Gomes P, Novo C, Barroso H, Taveira N - Retrovirology (2008)

Maximum-likelihood phylogenetic analysis. The phylogenetic tree was constructed with reference sequences from HIV-2 groups A, B and G, under the TVM+G+I evolutionary model, using the NNI heuristic search strategy and 1000 bootstrap replications. The triangles represent the compressed subtrees containing clonal sequences obtained from all samples collected for each patient. The length of the triangle represents the intra-patient nucleotide diversity and its thickness is proportional to the number of sequences. The bootstrap values supporting the internal branches are shown. The scale bar represents evolutionary distances in substitutions per site. The inset contains the subtrees of patient PTHCC1 (A), PTHCC20 (B) and PTHCC5 (C) (Yellow circle – 2003; green circle – 2004; blue circle – 2005).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2563025&req=5

Figure 1: Maximum-likelihood phylogenetic analysis. The phylogenetic tree was constructed with reference sequences from HIV-2 groups A, B and G, under the TVM+G+I evolutionary model, using the NNI heuristic search strategy and 1000 bootstrap replications. The triangles represent the compressed subtrees containing clonal sequences obtained from all samples collected for each patient. The length of the triangle represents the intra-patient nucleotide diversity and its thickness is proportional to the number of sequences. The bootstrap values supporting the internal branches are shown. The scale bar represents evolutionary distances in substitutions per site. The inset contains the subtrees of patient PTHCC1 (A), PTHCC20 (B) and PTHCC5 (C) (Yellow circle – 2003; green circle – 2004; blue circle – 2005).
Mentions: To investigate the molecular evolution of the HIV-2 env gene we have amplified, cloned and sequenced the env gene fragment coding for the C2, V3 and C3 regions using yearly samples collected from 18 patients followed prospectively for 2–4 years. A total of 431 clonal sequences were obtained from 18 patients (average of 13 sequences per patient per sampling year). Phylogenetic analysis showed that all sequences clustered together within HIV-2 group A and that each patient sequences formed monophyletic sub-clusters with high bootstrap supporting values (Figure 1). Phylogenetic analysis also showed that with the exceptions of patients PTHCC1, PTHCC5 and PTHCC20, sequences from most patients were not segregated according to sampling years, a clear indication that there were no major shifts in virus population structure from one year to the other.

Bottom Line: Variation of the C2V3C3-specific IgA response was inversely associated with variation in the number of N-glycosylation sites.C2V3C3-specific IgG antibodies are effective at reducing viral population size limiting the number of virus escape mutants.Our results provide new insights into the biology of HIV-2 and its relation with the human host and may have important implications for vaccine design.

View Article: PubMed Central - HTML - PubMed

Affiliation: URIA-CPM, Faculdade de Farmácia de Lisboa, Avenida das Forças Armadas, 1649-019 Lisbon, Portugal. pborrego@ff.ul.pt

ABSTRACT

Background: This study was designed to investigate, for the first time, the short-term molecular evolution of the HIV-2 C2, V3 and C3 envelope regions and its association with the immune response. Clonal sequences of the env C2V3C3 region were obtained from a cohort of eighteen HIV-2 chronically infected patients followed prospectively during 2-4 years. Genetic diversity, divergence, positive selection and glycosylation in the C2V3C3 region were analysed as a function of the number of CD4+ T cells and the anti-C2V3C3 IgG and IgA antibody reactivity

Results: The mean intra-host nucleotide diversity was 2.1% (SD, 1.1%), increasing along the course of infection in most patients. Diversity at the amino acid level was significantly lower for the V3 region and higher for the C2 region. The average divergence rate was 0.014 substitutions/site/year, which is similar to that reported in chronic HIV-1 infection. The number and position of positively selected sites was highly variable, except for codons 267 and 270 in C2 that were under strong and persistent positive selection in most patients. N-glycosylation sites located in C2 and V3 were conserved in all patients along the course of infection. Intra-host variation of C2V3C3-specific IgG response over time was inversely associated with the variation in nucleotide and amino acid diversity of the C2V3C3 region. Variation of the C2V3C3-specific IgA response was inversely associated with variation in the number of N-glycosylation sites.

Conclusion: The evolutionary dynamics of HIV-2 envelope during chronic aviremic infection is similar to HIV-1 implying that the virus should be actively replicating in cellular compartments. Convergent evolution of N-glycosylation in C2 and V3, and the limited diversification of V3, indicates that there are important functional constraints to the potential diversity of the HIV-2 envelope. C2V3C3-specific IgG antibodies are effective at reducing viral population size limiting the number of virus escape mutants. The C3 region seems to be a target for IgA antibodies and increasing N-linked glycosylation may prevent HIV-2 envelope recognition by these antibodies. Our results provide new insights into the biology of HIV-2 and its relation with the human host and may have important implications for vaccine design.

Show MeSH
Related in: MedlinePlus