Abstract
Numerous studies have suggested that an effective Hepatitis C Virus (HCV) vaccine must induce strong cytotoxic and IFN-γ+ T cell responses targeting the non-structural region of the virus. Most importantly, these responses must be able to migrate into and remain functional within the liver, an organ known to cause T cell tolerance. Using three novel HCV DNA vaccines encoding non-structural proteins NS4B, NS5A and NS5B, we assessed the ability of peripheral immunization to induce functional intrahepatic immunity both in the presence and absence of cognate HCV antigen expression within the liver. We have shown that these constructs induced potent HCV-specific CD4+ and CD8+ T cell responses in the spleen of C57BL/6 mice and that these responses were detected within the liver following peripheral immunization. Additionally, using a transfection method to express HCV antigen within the liver, we showed that intrahepatic HCV-specific T cells remained highly functional within the liver and retained the ability to become highly activated as evidenced by upregulation of IFN-γ and clearance of HCV protein expressing hepatocytes. Taken together, these findings suggest that peripheral immunization can induce potent HCV-specific T cell responses able to traffic to and function within the tolerant environment of the liver.
Highlights
Perhaps the greatest challenge in vaccine development for Hepatitis C Virus is that unlike other hepatitis viruses, such as Hepatitis A and Hepatitis B, where successful antibody-based vaccines have been created, protection against HCV infection does not appear to be antibody mediated [1,2]
We took a multi-step approach to design three different DNA vaccines able to induce potent cytotoxic and IFN-c+ HCV-specific T cell responses directed against the non-structural proteins, NS4B, NS5A and NS5B. We show that these constructs, pConNS4B, pConNS5A and pConNS5B are expressed in vitro and are able to induce strong HCV-specific T cell responses in the spleen
While there is strong agreement on the type of responses needed for an effective HCV vaccine, to date there has been little research aimed at elucidating whether vaccines targeting non-structural proteins other than NS3 can induce potent T cell responses within the liver
Summary
Perhaps the greatest challenge in vaccine development for Hepatitis C Virus is that unlike other hepatitis viruses, such as Hepatitis A and Hepatitis B, where successful antibody-based vaccines have been created, protection against HCV infection does not appear to be antibody mediated [1,2]. While it is known that strong intrahepatic HCV-specific T cell responses are correlated with clearance of acute infection, most HCV infected individuals fail to either mount or sustain these responses resulting in the progression to chronic infection [7] Part of this failure has been attributed to the tolerant immunological environment of the liver and its ability to negatively modulate T cell responses [8]. The liver is thought to induce tolerance by maintaining an environment of abundant IL-10 production [8] and low expression of costimulatory molecules [11,12] This immunmodulatory environment has been known to cause dysfunction and apoptosis of CD8+ T cells which, has been associated with liver-induced T cell tolerance to food, transplant and hepatotropic viral antigens [13,14,15,16]
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