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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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Evolution of the structure of C2-V3-C3 envelope region. Three-dimensional structures of C2-V3-C3 amino acid sequences from child 1 and 2 were generated by homology modelling using the three-dimensional structure of an unliganded SIV gp120 envelope glycoprotein as template. A) Superimposition of the structures of C2-V3-C3 of child 1 in 1998 (yellow), 2000 (blue) and 2003 (pale red); B) Superimposition of the structures of C2-V3-C3 of child 2 in 1992 (yellow), 1997 (blue) and 2001 (pale red). V3 loop and C2 and C3 stretches are indicated in the figures. C) Three-dimensional structures of C2-V3-C3 from child 1 (CT) in 2003 (blue) and child 2 (SC) in1997 (red). At this time both viruses were X4 and showed resistance to Nabs.
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Figure 5: Evolution of the structure of C2-V3-C3 envelope region. Three-dimensional structures of C2-V3-C3 amino acid sequences from child 1 and 2 were generated by homology modelling using the three-dimensional structure of an unliganded SIV gp120 envelope glycoprotein as template. A) Superimposition of the structures of C2-V3-C3 of child 1 in 1998 (yellow), 2000 (blue) and 2003 (pale red); B) Superimposition of the structures of C2-V3-C3 of child 2 in 1992 (yellow), 1997 (blue) and 2001 (pale red). V3 loop and C2 and C3 stretches are indicated in the figures. C) Three-dimensional structures of C2-V3-C3 from child 1 (CT) in 2003 (blue) and child 2 (SC) in1997 (red). At this time both viruses were X4 and showed resistance to Nabs.

Mentions: In long-term HIV-2 infected individuals the envelope V3 region adopts a significantly different structure in Nab-resistant isolates as compared to Nab-sensitive isolates, supporting a direct role of V3 conformation in the different susceptibility of these viruses to antibody neutralization [23]. To gain some insight into the structural evolution of the V3 region in the first years of HIV-2 infection and try to relate it to tropism and susceptibility to antibody neutralization, model structures of C2-V3-C3 regions from both children were generated by homology modelling using the three-dimensional structure of an unliganded SIV gp120 envelope glycoprotein as template. Remarkably, the V3 loop, which was characterized by a high content of irregular secondary structure in the first year of infection, converged to an similar β-hairpin structure at year five of infection in both infants and remained in this conformation until the last year of infection in child 2 (Figure 5 and Additional file 1: Table S1). The rate of acquisition of the β-hairpin conformation fully correlated with the rate of R5-to-X4 tropism transition and with the rate of escape from antibody neutralization.


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)

Evolution of the structure of C2-V3-C3 envelope region. Three-dimensional structures of C2-V3-C3 amino acid sequences from child 1 and 2 were generated by homology modelling using the three-dimensional structure of an unliganded SIV gp120 envelope glycoprotein as template. A) Superimposition of the structures of C2-V3-C3 of child 1 in 1998 (yellow), 2000 (blue) and 2003 (pale red); B) Superimposition of the structures of C2-V3-C3 of child 2 in 1992 (yellow), 1997 (blue) and 2001 (pale red). V3 loop and C2 and C3 stretches are indicated in the figures. C) Three-dimensional structures of C2-V3-C3 from child 1 (CT) in 2003 (blue) and child 2 (SC) in1997 (red). At this time both viruses were X4 and showed resistance to Nabs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Evolution of the structure of C2-V3-C3 envelope region. Three-dimensional structures of C2-V3-C3 amino acid sequences from child 1 and 2 were generated by homology modelling using the three-dimensional structure of an unliganded SIV gp120 envelope glycoprotein as template. A) Superimposition of the structures of C2-V3-C3 of child 1 in 1998 (yellow), 2000 (blue) and 2003 (pale red); B) Superimposition of the structures of C2-V3-C3 of child 2 in 1992 (yellow), 1997 (blue) and 2001 (pale red). V3 loop and C2 and C3 stretches are indicated in the figures. C) Three-dimensional structures of C2-V3-C3 from child 1 (CT) in 2003 (blue) and child 2 (SC) in1997 (red). At this time both viruses were X4 and showed resistance to Nabs.
Mentions: In long-term HIV-2 infected individuals the envelope V3 region adopts a significantly different structure in Nab-resistant isolates as compared to Nab-sensitive isolates, supporting a direct role of V3 conformation in the different susceptibility of these viruses to antibody neutralization [23]. To gain some insight into the structural evolution of the V3 region in the first years of HIV-2 infection and try to relate it to tropism and susceptibility to antibody neutralization, model structures of C2-V3-C3 regions from both children were generated by homology modelling using the three-dimensional structure of an unliganded SIV gp120 envelope glycoprotein as template. Remarkably, the V3 loop, which was characterized by a high content of irregular secondary structure in the first year of infection, converged to an similar β-hairpin structure at year five of infection in both infants and remained in this conformation until the last year of infection in child 2 (Figure 5 and Additional file 1: Table S1). The rate of acquisition of the β-hairpin conformation fully correlated with the rate of R5-to-X4 tropism transition and with the rate of escape from antibody neutralization.

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