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Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response.

Rocha C, Calado R, Borrego P, Marcelino JM, Bártolo I, Rosado L, Cavaco-Silva P, Gomes P, Família C, Quintas A, Skar H, Leitner T, Barroso H, Taveira N - Retrovirology (2013)

Bottom Line: Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous.Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed.Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2.

View Article: PubMed Central - HTML - PubMed

Affiliation: Unidade dos Retrovírus e Infecções Associadas, Centro de Patogénese Molecular, Faculdade de Farmácia de Lisboa, Lisboa, Portugal. ntaveira@ff.ul.pt.

ABSTRACT

Background: Differently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4⁺ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth.

Results: CD4⁺ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a β-hairpin structure were related with rate of escape from the neutralizing antibodies.

Conclusion: Our data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis.

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Neutralizing antibody response against heterologous primary isolates in child 1 over the course of infection. A) A heat map of the reciprocal log-transformed IC50 value of each plasma sample from child 1 (left) against a panel of five heterologous primary virus isolates with respective tropism (top) is shown. The reciprocal log10 IC50 value is colour-coded. The darkest colour indicates that neutralization above 50% was still detected with the highest plasma dilution tested (1/5120). The lightest colour indicates that there was no detectable neutralization above 50% with the lowest plasma dilution tested (1/40). n.d.–not done (due to lack of plasma); B) Dot-plot graphic showing the mean and standard deviation of the reciprocal log10 IC50 values obtained against R5 and X4 isolates indicated in A. Mann–Whitney U test was used to compare the median log10 reciprocal IC50 values.
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Figure 3: Neutralizing antibody response against heterologous primary isolates in child 1 over the course of infection. A) A heat map of the reciprocal log-transformed IC50 value of each plasma sample from child 1 (left) against a panel of five heterologous primary virus isolates with respective tropism (top) is shown. The reciprocal log10 IC50 value is colour-coded. The darkest colour indicates that neutralization above 50% was still detected with the highest plasma dilution tested (1/5120). The lightest colour indicates that there was no detectable neutralization above 50% with the lowest plasma dilution tested (1/40). n.d.–not done (due to lack of plasma); B) Dot-plot graphic showing the mean and standard deviation of the reciprocal log10 IC50 values obtained against R5 and X4 isolates indicated in A. Mann–Whitney U test was used to compare the median log10 reciprocal IC50 values.

Mentions: Notably, child 1 also produced neutralizing antibodies that potently neutralized several heterologous primary HIV-2 isolates. Again, the heterologous Nabs were significantly more effective against R5 strains than against X4 strains [median (range) of reciprocal log10 IC50 neutralization titers against R5 and X4 isolates were 3.5 (1.6-4.0) and 2.5 (1.6-4.0), respectively, P = 0.0041] (Figure 3).


Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response.

Rocha C, Calado R, Borrego P, Marcelino JM, Bártolo I, Rosado L, Cavaco-Silva P, Gomes P, Família C, Quintas A, Skar H, Leitner T, Barroso H, Taveira N - Retrovirology (2013)

Neutralizing antibody response against heterologous primary isolates in child 1 over the course of infection. A) A heat map of the reciprocal log-transformed IC50 value of each plasma sample from child 1 (left) against a panel of five heterologous primary virus isolates with respective tropism (top) is shown. The reciprocal log10 IC50 value is colour-coded. The darkest colour indicates that neutralization above 50% was still detected with the highest plasma dilution tested (1/5120). The lightest colour indicates that there was no detectable neutralization above 50% with the lowest plasma dilution tested (1/40). n.d.–not done (due to lack of plasma); B) Dot-plot graphic showing the mean and standard deviation of the reciprocal log10 IC50 values obtained against R5 and X4 isolates indicated in A. Mann–Whitney U test was used to compare the median log10 reciprocal IC50 values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016255&req=5

Figure 3: Neutralizing antibody response against heterologous primary isolates in child 1 over the course of infection. A) A heat map of the reciprocal log-transformed IC50 value of each plasma sample from child 1 (left) against a panel of five heterologous primary virus isolates with respective tropism (top) is shown. The reciprocal log10 IC50 value is colour-coded. The darkest colour indicates that neutralization above 50% was still detected with the highest plasma dilution tested (1/5120). The lightest colour indicates that there was no detectable neutralization above 50% with the lowest plasma dilution tested (1/40). n.d.–not done (due to lack of plasma); B) Dot-plot graphic showing the mean and standard deviation of the reciprocal log10 IC50 values obtained against R5 and X4 isolates indicated in A. Mann–Whitney U test was used to compare the median log10 reciprocal IC50 values.
Mentions: Notably, child 1 also produced neutralizing antibodies that potently neutralized several heterologous primary HIV-2 isolates. Again, the heterologous Nabs were significantly more effective against R5 strains than against X4 strains [median (range) of reciprocal log10 IC50 neutralization titers against R5 and X4 isolates were 3.5 (1.6-4.0) and 2.5 (1.6-4.0), respectively, P = 0.0041] (Figure 3).

Bottom Line: Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous.Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed.Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2.

View Article: PubMed Central - HTML - PubMed

Affiliation: Unidade dos Retrovírus e Infecções Associadas, Centro de Patogénese Molecular, Faculdade de Farmácia de Lisboa, Lisboa, Portugal. ntaveira@ff.ul.pt.

ABSTRACT

Background: Differently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4⁺ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth.

Results: CD4⁺ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a β-hairpin structure were related with rate of escape from the neutralizing antibodies.

Conclusion: Our data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis.

Show MeSH
Related in: MedlinePlus