title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Cheila
authors.initials: C
authors.lastname: Rocha
authors.forename: Rita
authors.initials: R
authors.lastname: Calado
authors.forename: Pedro
authors.initials: P
authors.lastname: Borrego
authors.forename: José Maria
authors.initials: JM
authors.lastname: Marcelino
authors.forename: Inês
authors.initials: I
authors.lastname: Bártolo
authors.forename: Lino
authors.initials: L
authors.lastname: Rosado
authors.forename: Patrícia
authors.initials: P
authors.lastname: Cavaco-Silva
authors.forename: Perpétua
authors.initials: P
authors.lastname: Gomes
authors.forename: Carlos
authors.initials: C
authors.lastname: Família
authors.forename: Alexandre
authors.initials: A
authors.lastname: Quintas
authors.forename: Helena
authors.initials: H
authors.lastname: Skar
authors.forename: Thomas
authors.initials: T
authors.lastname: Leitner
authors.forename: Helena
authors.initials: H
authors.lastname: Barroso
authors.affiliation: Unidade dos Retrovírus e Infecções Associadas, Centro de Patogénese Molecular, Faculdade de Farmácia de Lisboa, Lisboa, Portugal. ntaveira@ff.ul.pt.
authors.forename: Nuno
authors.initials: N
authors.lastname: Taveira
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D000940:Antigenic Variation; D002648:Child; D002675:Child, Preschool; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015498:HIV-2 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus