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While a persistent infection is generally associated with a weak CD4+ and CD8+ T cell response during the acute phase, there is no good explanation as to why this response is strong enough in 20% of acutely infected people such that they spontaneously resolve the infection. However, the immune system partially controls the viral infection but due to a long\u2010lasting inflammatory milieu, hepatic damage occurs. During the chronic phase of the infection, HCV does not seem to be cytopathic. This aspect is still controversial as the virus was linked to the development of cholestatic syndrome or acute lobular hepatitis after liver transplant in HCV infected patients.<\/jats:p><jats:p>The development of new experimental systems such as HCV pseudoparticles, genomic replicon and transfected cell lines have improved our vision of the virus cycle as well as the understanding of the mechanism of persistence. However, a convincing explanation for the chronicity of the infection in the presence of a functional immune response is still missing and is an important area of research to understand HCV immune pathogenesis.<\/jats:p><jats:p>Future research should dissect mechanisms that lead to quantitatively or qualitatively inadequate immune responses, the role of the high variability of the virus, the relevance of host's genetic factors and mechanisms of immunosuppression induced by the virus. 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