Publicação
Analysis of antibody neutralization specificities in human immunodeficiency virus type 2 infection
| Resumo: | Dynamics of the neutralizing antibody response and resulting HIV-2 escape during acute and chronic infections and their impact on viral evolution and disease progression remain unknown. The aims of this thesis were: characterize Nab response and molecular and phenotypic evolution of HIV-2 in early infection, investigate Nab responses in HIV-2 chronically infected patients with memory B cell imbalances and characterize the neutralization phenotype of HIV-2 X4-tropic isolates from diverse disease stages. Broad and potent Nabs are elicited very early in HIV-2 infection, the potency of this response being associated with high evolutionary rates. Nab escape was associated with R5-to-X4 switch, increased diversity in V1 and V3 regions and changes in V3 conformation. These findings show that Nabs are the main driver of the rapid molecular and phenotypic evolution of HIV-2 in early infection. Despite the loss of memory B cells observed with disease progression, broad and potent Nabs were elicited throughout HIV-2 infection. Nabs were found to target the C2V3C3 envelope region and, in advanced disease stage, the gp36 ectodomain. These data suggest a role for other B cell subsets in the production and perpetuation of Nabs. HIV-2 X4-tropic viruses were found to be significantly more Nab resistant than R5 viruses (independently of disease stage) and late infection X4 isolates were significantly more Nab resistant than early infection X4 viruses. X4-tropism was associated with sequence changes and significant gain in the V3 loop secondary structure. The results prove that Nab resistance is an intrinsic feature of X4-tropic HIV-2 isolates, acquired through infection period, and is associated with amino acid and conformational changes in the V3 loop that favour R5-to-X4 switch. In conclusion, Nab responses emerge very early in infection, persist despite memory B cells imbalances and drive tropism switch, supporting a major role for Nabs in HIV-2 evolution.O Vírus da Imunodeficiência Humana do tipo 2 (HIV-2) foi identificado pela primeira vez como agente causal da Síndrome de Imunodeficiência Adquirida (SIDA) em 1986 numa colaboração entre cientistas e clínicos portugueses (Professora Maria Odette Santos Ferreira da Faculdade de Farmácia de Lisboa e Professor José Luís Champalimaud do Hospital Egas Moniz) e franceses (equipe de investigadores liderada pelo Professor Luc Montagnier do Instituto Pasteur em Paris). |
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| Autores principais: | Rocha, Cheila Cristina Pereira Alves, 1978- |
| Assunto: | Teses de doutoramento - 2013 |
| Ano: | 2013 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Dynamics of the neutralizing antibody response and resulting HIV-2 escape during acute and chronic infections and their impact on viral evolution and disease progression remain unknown. The aims of this thesis were: characterize Nab response and molecular and phenotypic evolution of HIV-2 in early infection, investigate Nab responses in HIV-2 chronically infected patients with memory B cell imbalances and characterize the neutralization phenotype of HIV-2 X4-tropic isolates from diverse disease stages. Broad and potent Nabs are elicited very early in HIV-2 infection, the potency of this response being associated with high evolutionary rates. Nab escape was associated with R5-to-X4 switch, increased diversity in V1 and V3 regions and changes in V3 conformation. These findings show that Nabs are the main driver of the rapid molecular and phenotypic evolution of HIV-2 in early infection. Despite the loss of memory B cells observed with disease progression, broad and potent Nabs were elicited throughout HIV-2 infection. Nabs were found to target the C2V3C3 envelope region and, in advanced disease stage, the gp36 ectodomain. These data suggest a role for other B cell subsets in the production and perpetuation of Nabs. HIV-2 X4-tropic viruses were found to be significantly more Nab resistant than R5 viruses (independently of disease stage) and late infection X4 isolates were significantly more Nab resistant than early infection X4 viruses. X4-tropism was associated with sequence changes and significant gain in the V3 loop secondary structure. The results prove that Nab resistance is an intrinsic feature of X4-tropic HIV-2 isolates, acquired through infection period, and is associated with amino acid and conformational changes in the V3 loop that favour R5-to-X4 switch. In conclusion, Nab responses emerge very early in infection, persist despite memory B cells imbalances and drive tropism switch, supporting a major role for Nabs in HIV-2 evolution.O Vírus da Imunodeficiência Humana do tipo 2 (HIV-2) foi identificado pela primeira vez como agente causal da Síndrome de Imunodeficiência Adquirida (SIDA) em 1986 numa colaboração entre cientistas e clínicos portugueses (Professora Maria Odette Santos Ferreira da Faculdade de Farmácia de Lisboa e Professor José Luís Champalimaud do Hospital Egas Moniz) e franceses (equipe de investigadores liderada pelo Professor Luc Montagnier do Instituto Pasteur em Paris). |
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