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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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Frequency and distribution of potential N-glycosylation sites in the C2, V3 and C3 regions along the course of infection. The frequency and distribution of potential N-linked glycosylation sites in the C2, V3 and C3 regions are shown in each infection year. Higher frequency glycosylation sites are shown in bold letters. Sites were numbered according to the reference HIV-2ALI strain. (na, not available)
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Figure 3: Frequency and distribution of potential N-glycosylation sites in the C2, V3 and C3 regions along the course of infection. The frequency and distribution of potential N-linked glycosylation sites in the C2, V3 and C3 regions are shown in each infection year. Higher frequency glycosylation sites are shown in bold letters. Sites were numbered according to the reference HIV-2ALI strain. (na, not available)

Mentions: Since the glycosylation pattern of the HIV-1 env gene may influence neutralization escape to the immune system, viral tropism and clinical progression [32,36,54-57], we determined the number of potential N-glycosylation sites in our sequences and examined its variation as a function of time and other parameters analyzed in this study. The number of N-glycosylation sites ranged from 5 to 8 (median, 7) and tended to be conserved along the infection in each patient, the exception being patient PTHCC1 with an increase in two sites over the three years of follow up (Figure 3). The number of glycosylation sites varied significantly between C2, V3 and C3 (p < 0.001), being concentrated particularly in C2 (p < 0.001) (n = 18). At the intra- and inter-patient level, the most conserved N-glycosylation sites were located in C2 and V3. With one exception, all sites that varied over time were located in C3. The number of N-linked glycosylation sites was directly associated with the number of positively selected sites (r2 = 0.301; p = 0.018).


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)

Frequency and distribution of potential N-glycosylation sites in the C2, V3 and C3 regions along the course of infection. The frequency and distribution of potential N-linked glycosylation sites in the C2, V3 and C3 regions are shown in each infection year. Higher frequency glycosylation sites are shown in bold letters. Sites were numbered according to the reference HIV-2ALI strain. (na, not available)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Frequency and distribution of potential N-glycosylation sites in the C2, V3 and C3 regions along the course of infection. The frequency and distribution of potential N-linked glycosylation sites in the C2, V3 and C3 regions are shown in each infection year. Higher frequency glycosylation sites are shown in bold letters. Sites were numbered according to the reference HIV-2ALI strain. (na, not available)
Mentions: Since the glycosylation pattern of the HIV-1 env gene may influence neutralization escape to the immune system, viral tropism and clinical progression [32,36,54-57], we determined the number of potential N-glycosylation sites in our sequences and examined its variation as a function of time and other parameters analyzed in this study. The number of N-glycosylation sites ranged from 5 to 8 (median, 7) and tended to be conserved along the infection in each patient, the exception being patient PTHCC1 with an increase in two sites over the three years of follow up (Figure 3). The number of glycosylation sites varied significantly between C2, V3 and C3 (p < 0.001), being concentrated particularly in C2 (p < 0.001) (n = 18). At the intra- and inter-patient level, the most conserved N-glycosylation sites were located in C2 and V3. With one exception, all sites that varied over time were located in C3. The number of N-linked glycosylation sites was directly associated with the number of positively selected sites (r2 = 0.301; p = 0.018).

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