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Polimorfismos da regiĆ£o da integrase, do gene pol, em doentes infectados por VIH-1
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A integrase do VIH-1 Ć© a enzima responsĆ”vel pela integraĆ§Ć£o do ADN viral no ADN da cĆ©lula hospedeira. Este processo Ć© indispensĆ”vel Ć replicaĆ§Ć£o viral, desenvolvendo-se em duas etapas independentes, o processamento 3Ā“ e a transferĆŖncia de cadeias catalisadas pela integrase. A compreensĆ£o das interacƧƵes entre a integrase e o ADN e a cinĆ©tica da formaĆ§Ć£o dos complexos de prĆ©-integraĆ§Ć£o evidenciaram a necessidade de descobrir inibidores das ligaƧƵes do complexo integrase/ADN. Esta necessidade, permitiu desenvolver o Raltegravir e o Elvitagravir como inibidores potentes da transferĆŖncia de cadeias e consequentemente da replicaĆ§Ć£o viral in vivo. Estes fĆ”rmacos porĆ©m, nĆ£o escapam aos fenĆ³menos de resistĆŖncia.
Mais de 40 substituiƧƵes na integrase foram associadas ao desenvolvimento de resistĆŖncia ao Raltegravir e/ou elvitagravir, in vitro. Algumas destas alteraƧƵes foram tambĆ©m encontradas in vivo em doentes com falĆŖncia terapĆŖutica aos inibidores da integrase. Os polimorfismos do gene da integrase ocorrem de forma natural, podendo ter implicaƧƵes importantes no desenvolvimento de inibidores da integrase. Foi objectivo deste estudo a determinaĆ§Ć£o da prevalĆŖncia de polimorfismos em doentes nĆ£o tratados com inibidores da integrase e a
frequĆŖncia de substituiĆ§Ć£o de aminoĆ”cidos que ocorrem de forma natural em posiƧƵes associadas a resistĆŖncia. Foram indentificadas as posiƧƵes polimĆ³rficas do gene pol da integrase em doentes nĆ£o tratados com inibidores da integrase, confirmando-se a ausĆŖncia de
mutaƧƵes associadas a resistĆŖncia nestes mesmos doentes. A percentagem de polimorfismos variou de acordo com a regiĆ£o analisada, sendo a regiĆ£o C-terminal a mais variĆ”vel. A anĆ”lise
mais detalhada do subtipo G contribuiu de forma significativa para caracterizar os polimorfismos existentes na populaĆ§Ć£o de doentes VIH-1 portuguesa. A utilizaĆ§Ć£o do Ćndice de Jaccard permitiu de forma inequĆvoca demonstrar a associaĆ§Ć£o entre posiƧƵes polimĆ³rficas e
verificar como essas associaƧƵes poderĆ£o evoluir.
The integrase catalyzes the integration of HIV-1 DNA into the host cell chromosome in a process which is essential for viral replication. Integrase performs two independent reactions, 3 Ģ-end processing and strand transfer. Deciphering the structural determinants of the interaction between integrase and its substrates as well as kinetics of this interaction shed light on the importance for pharmacological agents to target the integrase-viral DNA complex. This approach led to the development of Raltegravir and elvitagravir which turned out to be powerful inhibitors of strand transfer both in vitro and in vivo. However, like others ARVs, these compounds face resistance phenome non. Among them, about 40 substitutions in vitro have been specifically associated with the development of resistance to Raltegravir and/or Elvitagravir, some of them were also found in vivo in patients failing such integrase inhibitors. Naturally occurring integrase gene polymorphisms may have important implications for integrase inhibitors development. This study evaluated clinical HIV-1 strains from integrase inhibitors naĆÆve patients, to determine the prevalence of integrase gene polymorphisms, and the frequency of naturally occurring amino acid substitution at positions associated with integrase resistance. Polymorphic posit ions at integrase region of pol gene were identified in patients not treated with integrase inhibitors. The absence of resistance mutations to these compounds was confirmed. The percentage of polymorphisms was different within integrase regions, being the C-terminal region the one with the highest variability. Detailed analysis of G subtype contributed significantly to characterise the polymorphisms in Portuguese HIV-1 infected patients. Jacard index was used to demonstrate association between polymorphic positions and verify how those associations may evolve.
The integrase catalyzes the integration of HIV-1 DNA into the host cell chromosome in a process which is essential for viral replication. Integrase performs two independent reactions, 3 Ģ-end processing and strand transfer. Deciphering the structural determinants of the interaction between integrase and its substrates as well as kinetics of this interaction shed light on the importance for pharmacological agents to target the integrase-viral DNA complex. This approach led to the development of Raltegravir and elvitagravir which turned out to be powerful inhibitors of strand transfer both in vitro and in vivo. However, like others ARVs, these compounds face resistance phenome non. Among them, about 40 substitutions in vitro have been specifically associated with the development of resistance to Raltegravir and/or Elvitagravir, some of them were also found in vivo in patients failing such integrase inhibitors. Naturally occurring integrase gene polymorphisms may have important implications for integrase inhibitors development. This study evaluated clinical HIV-1 strains from integrase inhibitors naĆÆve patients, to determine the prevalence of integrase gene polymorphisms, and the frequency of naturally occurring amino acid substitution at positions associated with integrase resistance. Polymorphic posit ions at integrase region of pol gene were identified in patients not treated with integrase inhibitors. The absence of resistance mutations to these compounds was confirmed. The percentage of polymorphisms was different within integrase regions, being the C-terminal region the one with the highest variability. Detailed analysis of G subtype contributed significantly to characterise the polymorphisms in Portuguese HIV-1 infected patients. Jacard index was used to demonstrate association between polymorphic positions and verify how those associations may evolve.
DescriĆ§Ć£o
Palavras-chave
CiĆŖncias biomĆ©dicas DoenƧas infecciosas HIV Gene pol Enzimas Polimorfismo
Contexto Educativo
CitaĆ§Ć£o
Editora
Instituto de Higiene e Medicina Tropical