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Doctoral Thesis
DOI
10.11606/T.42.2012.tde-13112012-083943
Document
Author
Full name
Atila Iamarino
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2012
Supervisor
Committee
Zanotto, Paolo Marinho de Andrade (President)
Bentancor, Gonzalo Jose Bello
Pardini, Maria Inês de Moura Campos
Pierulivo, Enrique Mario Boccardo
Sobreira, Tiago José Paschoal
Title in Portuguese
Análise e caracterização molecular, estrutural e populacional de proteases de HIV-1 do Estado de São Paulo.
Keywords in Portuguese
HIV
Microbiologia
Virologia
Vírus
Vírus de RNA
Abstract in Portuguese
Apesar dos esforços para controlar a infecção por HIV-1, na América do Sul, diversos recombinantes tem sido descritos, principalmente entre os subtipos B e F. Durante a tarefa coordenada de HIV-1 VGDN, foram encontrados diversos novos recombinantes BF no estado de São Paulo, sendo a maioria deles com a protease F. Técnicas filogenéticas usadas em integrases destes pacientes demonstraram que sequências recombinantes com perfis similares surgiram em diferentes eventos de recombinação. Análises filodinâmicas de amostras argentinas apontaram um crescimento contínuo de recombinantes com proteases F após a introdução da terapia intensiva, enquanto o subtipo B deixou de crescer. Dados estruturais e de interação de proteases F resistentes com o inibidor nelfinavir obtidos por dinâmica molecular sugeriram que polimorfismos do subtipo F podem atuar como restauradores de atividade ou acentuar a perda de afinidade pelo inibidor. Um vetor recombinante pNL4-3 com parte do gene gag e a protease do subtipo F foi construído, permitindo a comparação de seu efeito no fitness viral.
Title in English
Molecular, structural and populational analysis and characterization of HIV-1 proteases at Sao Paulo state.
Keywords in English
HIV
Microbiology
Virology
Virus
Virus RNA
Abstract in English
Despite general efforts to control HIV-1 infections, many recombinants have been described among B and F subtype in South America. During the VGDN HIV task in São Paulo state, a large number of new BF recombinants was found, most of which harbor a subtype F protease. Phylogenetic analysis of integrase genes from these patients showed distinct origins for similar recombinant regions. Phylodynamic analysis suggested that after HAART introduction in Argentina BF recombinants with F protease depicted a sustained growth, while subtype B had diminished in growth.. Moreover, structural data from proteases after HAART introduction, while subtype B had diminished growth. Subtype F proteases structure and nelfinavir interaction measured by molecular dynamics suggested that polymorphisms of this subtype may restore enzyme activity or decrease even further inhibitor affinity. A pNL4-3 recombinant vector with most of gag gene and a protease of subtype F was made, which allows the comparison of its effects on viral fitness.
 
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Publishing Date
2013-02-08
 
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