Efecto del tratamiento antirretroviral combinado, sobre la activación /inflamación sistemática en los pacientes con infección VIH; Potencial efecto inmunomodulador de Maraviroc. Factores inmunológicos asociados

Resumen

Los sujetos infectados por el virus de la inmunodeficiencia humana (VIH) que han sido tratados con terapia antirretroviral combinada (cART) han alcanzado una mayor esperanza de vida y supervivencia. Además este cART supresor de la viremia del VIH, mantenido durante un suficiente periodo de tiempo, ha logrado la normalización de las células T CD4+ en la mayoría de los pacientes y la reducción de la morbilidad y mortalidad asociada a SIDA, pero sin embargo no ha logrado descender la mortalidad no SIDA; en comparación con población general no infectada por el VIH. Además, el cART no es capaz de normalizar ciertos parámetros inmunológicos asociados a progresión de la enfermedad VIH. En la infección por VIH la activación inmune es un componente esencial de progresión de enfermedad. El origen de esta activación inmune persistente todavía no está claro. Se ha propuesto como potencial estímulo que causaría la activación inmunitaria el incremento de productos circulantes de origen microbiano durante la infección crónica por VIH, que reflejaría traslocación bacteriana desde el intestino. Varios parámetros se han usado indistintamente para determinar la traslocación bacteriana; los más comúnmente usados han sido lipopolisacáridos bacterianos (LPS) y CD14 soluble (CD14s). En la presente Tesis Doctoral, hemos analizado un tratamiento con Maraviroc (MVC), fármaco antagonista de CCR5. Durante un régimen consistente en la administración de MVC durante 8 días en monoterapia; hemos podido determinar los efectos específicos de un bloqueo del correceptor CCR5 en varios biomarcadores asociados a la progresión del VIH. En los pacientes que indetectabilizaron la carga viral durante esta monoterapia se observó un incremento en la activación y senescencia de células T CD8+, y un perfil más favorable en los niveles de dímero-D y CD14s. Después de 12 semanas bajo un cART que incluía MVC se incrementó significativamente el número absoluto de células T CD8+ y se preservaron los niveles de activación y senescencia CD4+ cuando se comparaban los pacientes bajo este régimen con un grupo control. Y de igual forma en un régimen que incluía MVC disminuyeron los niveles de CD14s cuando se comparó con un régimen sin MVC. Este trabajo se ha abordado en un manuscrito publicado como ¿Effect of maraviroc on HIV disease progression-related biomarkers¿ [MC. Romero-Sánchez, et al. Antimicrob Agents Chemother. 2012]. Ligando al anterior hallazgo, en la presente tesis doctoral hemos encontrado una asociación entre los niveles de virus con tropismo X4 y los niveles de activación de las células T CD4+. Esto ha supuesto un hallazgo importante en una laguna de conocimiento controvertida en la literatura, y esto datos animan a diseñar estrategias para la reducción de esta activación o fármacos tropismo-específicos y aumentar así el tiempo que los pacientes VIH+ se podrían beneficiar de MVC. Este objetivo se llevó a cabo en el estudio: ¿Asociación de un determinado tropismo vírico con las características inmunológicas en pacientes con infección VIH¿ [MC. Romero-Sánchez, et al, manuscrito en preparación, 2014]. Por otro lado, hemos comprobado en la presente tesis, que CD14s y LPS no marcan lo mismo, sino que CD14s refleja translocación bacteriana sólo cuando hay un débil estado inmunológico, y que además es CD14s el que más se relaciona con marcadores de progresión de la enfermedad; esto añade a nuestro primer estudio un valor más al efecto inmunodulador que se observa en el grupo que respondió a MVC y no en el grupo control; tanto en monoterapia como contenido en un cART a más largo pazo. Que conozcamos, sólo un estudio había descrito el efecto a largo plazo de un cART en los niveles de CD14s, pero las condiciones inmunovirológicas al inicio del cART de la población no se consideraron para este análisis, con los resultados obtenidos en otro trabajo abordado también en esta tesis, hemos demostrado que ni tras 5 años de tratamiento supresor se logra normalizar los valores de CD14s. Esto sugiere que puede haber un daño irreversible que estaría induciendo una activación persistente de monocitos tempranamente tras la infección. Ambos trabajos han sido publicados como ¿Different biological significance of sCD14 and LPS in HIV-infection: importance of the immunovirology stage and association with HIV-disease progression markers¿ [MC. Romero-Sánchez, et al. J Infect. 2012] y ¿Long-term suppressive combined antiretroviral treatment does not normalize the serum level of soluble CD14¿ [G. Méndez-Lagares, M.C. Romero-Sánchez, et al. J Infect Dis. 2012]. Finalmente, debido a los potenciales efectos beneficiosos de MVC hallados anteriormente, y porque un régimen antiretroviral sin análogos de nucleótidos podría evitar potenciales toxicidades, el escenario de pacientes infectados por VIH bajo cART con carga viral suprimida ha sido el ideal para probar el efecto de un cambio de régimen en biomarcadores de inflamación asociados a inflamación y progresión de la enfermedad VIH. Por ello en la presente tesis doctoral demostramos que el cambio es seguro y mantiene la supresión viral. Pero además se consigue tras 24 semanas una reducción en marcadores de inflamación. Hasta ahora esto no se había demostrado y abre una nueva ventana de oportunidad en la segunda era TARGA. Se sabe que el cART no es capaz de normalizar ciertos parámetros inmunes y que no reduce el riesgo de enfermedad no SIDA ; además nosotros hemos visto que normaliza CD14s ni tras 5 años, pero estos resultados apoyan el estudio de nuevas estrategias y terapias encaminadas a la reducción de estos parámetros. Esto se ha abordado en el manuscrito ¿Maintenance of virologic efficacy and decrease in levels of inflammatory markers after switching aviremic HIV-infected patients to an NRTI-sparing bitherapy¿ [MC. Romero-Sánchez, et al, manuscrito enviado en marzo de 2014]. Bibliografía: 1. Palella FJ, Jr., Delaney KM, Moorman AC, et al. 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