Publication: Marcadores genéticos y dominios conservados en la proteína de la cápside de las distintas variantes del VIH
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2019-06-26
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Abstract
La proteína CA de gag que forma la cápside del VIH posee un papel estructural y funcional esencial para el ciclo viral, resultando un interesante objetivo para el diseño de test moleculares diagnósticos y nuevas drogas antirretrovirales. En este trabajo estudiamos en detalle la conservación de esta proteína y de los elementos de su estructura secundaria. Localizamos los marcadores genéticos asociados a cada variante del VIH-1 y VIH-2 y los polimorfismos en aminoácidos clave para su función descritos en la literatura. También evaluamos la utilidad de secuencias de la CA para clasificar correctamente las variantes del VIH por análisis filogenético. Para todo ello se descargaron 39.010 secuencias de la proteína CA de la base de datos del Laboratorio Nacional de los Álamos de EE.UU de todas las variantes del VIH (tipos, grupos, subtipos, sub-subtipos y CRFs) y se analizaron utilizando una nueva herramienta bioinformática desarrollada en el laboratorio y verificada durante este estudio. CA presentó una alta conservación en las 105 variantes analizadas, encontrando estructuras menos conservadas como la horquilla-ß, la hélice-α 6 y el loop de unión a ciclofilina A. Se encontraron marcadores genéticos de variante en todos los tipos, subtipos, sub-subtipos y recombinantes del VIH. Se hallaron mutaciones en posiciones relevantes para la funcionalidad de estructuras destacadas de CA y en residuos altamente conservados cuyos polimorfismos se asocian a defectos del ensamblaje de la cápside inmadura según la literatura. Por último, se constató que CA es una buena región para caracterizar gran parte de las variantes del VIH.
The CA gag protein that forms the HIV capsid has an essential structural and functional role for the viral cycle, being an interesting objective for the design of diagnostic molecular tests and new antiretroviral drugs. In this work we studied in detail the conservation of this protein and of the elements in its secondary structure. We located the genetic markers associated with each HIV-1 and HIV-2 variant and the polymorphisms in key aminoacids for its functions described in the literature. We also evaluated its usefulness to correctly classify HIV variants by phylogenetic analysis. For this purpose, we downloaded 39.010 CA sequences from all HIV variants (types, groups, subtypes, sub-subtypes and CRFs) from the US Los Alamos HIV database and we analyzed them using a new bioinformatics tool developed in the laboratory and verified during this study. CA presented a high conservation in the 105 analyzed HIV variants. We identified structures with lower conservation such as the ß hairpin, the α helix 6 and the cyclophilin A binding loop. HIV-1 variant associated genetic markers were found in all types, subtypes, sub-subtypes and HIV CRFs. We found mutations in CA residues relevant for the functionality of CA structures and in highly conserved residues whose polymorphisms have been associated in the literature to defective assembly of the immature capsid. Finally, we found that CA coding región is a good region to characterize a large number of HIV variants.
The CA gag protein that forms the HIV capsid has an essential structural and functional role for the viral cycle, being an interesting objective for the design of diagnostic molecular tests and new antiretroviral drugs. In this work we studied in detail the conservation of this protein and of the elements in its secondary structure. We located the genetic markers associated with each HIV-1 and HIV-2 variant and the polymorphisms in key aminoacids for its functions described in the literature. We also evaluated its usefulness to correctly classify HIV variants by phylogenetic analysis. For this purpose, we downloaded 39.010 CA sequences from all HIV variants (types, groups, subtypes, sub-subtypes and CRFs) from the US Los Alamos HIV database and we analyzed them using a new bioinformatics tool developed in the laboratory and verified during this study. CA presented a high conservation in the 105 analyzed HIV variants. We identified structures with lower conservation such as the ß hairpin, the α helix 6 and the cyclophilin A binding loop. HIV-1 variant associated genetic markers were found in all types, subtypes, sub-subtypes and HIV CRFs. We found mutations in CA residues relevant for the functionality of CA structures and in highly conserved residues whose polymorphisms have been associated in the literature to defective assembly of the immature capsid. Finally, we found that CA coding región is a good region to characterize a large number of HIV variants.