Infeccion de las celulas dendriticas como estrategia de escape del virus de la hepatitis ccaracterizacion de los mecanismos e implicaciones para el desarrollo de vacunas

Resumen

#TITULO: INFECCIÓN DE LAS CÉLULAS DENDRITICAS COMO ESTRATEGIA DE ESCAPE DEL VIRUS DE LA HEPATITITS C: CARACTERIZACIÓN DE LOS MECANISMOS E IMPLICACIONES PARA EL DESARROLLO DE VACUNAS #RESUMEN: Hepatitis C virus (HCV) is an enveloped, single-stranded RNA virus belonging to the family Flaviviridae that is responsible for the majority of non-A, non-B hepatitis, infection by HCV is characterized by the ability to cause chronic hepatitis which may progress to liver cirrhosis and eventually to hepatocellular carcinoma. It has been suggested that HCV manipulates the immune system specifically suppressing the antiviral T-cell immunity. Infection of professional antigen presenting cells such as dendritic cells (dc) has been proposed among the strategies used by HCV to evade immunity. We show here that immunization of mice with immature DC transduced with an adenovirus encoding HCV core and El proteins (AdCEl) induced lower CD4+- and CD8+-t-cell responses than immunization with DC transduced with a control adenovirus encoding NS3 protein (AdNS3). No differences were detected when animals were immunized with mature DC subsequently transduced with AdCEl or AdNS3. According to these findings, we observed that the expression of CE1 in DC inhibited their maturation induced by tumor necrosis factor alpha or by CD40L but not that induced by lipopolysaccharide. our results suggest that HCV CE1 proteins modulate T-cell responses by decreasing the stimulatory ability of DC in vivo via inhibition of their physiological maturation pathways. Development of vaccination strategies against hepatitis C virus (HCV) is of paramount importance. With this aim, we tested the ability of DC activating reagents polyinosinic-polycytidylic acid (poly(i:C)) and an anti-CD40 agonistic antibody, as adjuvants to induce t-cell responses against HCV. immumzation of mice with these adjuvants induced dendritic cell maturation in vivo and activation of NK cells. The administration of these adjuvants plus HCV antigens (peptides or NS3 protein) had a synergistic effect on the induction of anti-HCV CD4+- and CD8+ t-cell responses with a Th1 cytokine profile. However, only, immunization with NS3 protein was able to induce cd8 responses able to recognize cells expressing HCV antigens endogenously. Finally, this combined immunization protocol afforded long-lasting t-cell responses. Since DC are the most potent antigen presenting cells, immunization with these cells loaded with viral antigens offers a new approach for induction of antiviral immunity. Here we show that immunization with DC transfected with AdNS3 induced multiepitopic CD4 Th1 and CD8 T-cell responses in different mouse strains. These responses protected mice against infection with a recombinant vaccinia virus encoding HCV genes and prevented growth of a tumor expressing HCV proteins in short- and long-term experiments. Moreover, immunization with AdNS3-transfected DC did not induce anti-adenoviral antibodies and elicited T-cell responses even in the presence of pre-existing anti-adenoviral antibodies. Finally, responses induced by this protocol down-regulated the expression of HCV RNA in the liver. In conclusion, DC transfected with AdNS3 may prove to be an efficient anti-HCV vaccine.