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Hepatitis C virus (HCV)-RNA detection in peripheral blood mononuclear cells (PBMCs) after recovery from HCV infection, is a type of occult HCV infection although is unclear how the viral persistence in PBMCs affects HCV-specific T-cell responses. The aim of this study was to investigate if cellular immune responses are modified by HCV persistence in PBMCs.HCV-specific CD4+ and CD8+ T-cell responses against six HCV peptides, situated within the non-structural (NS) proteins NS3, NS4b and NS5b, were measured by flow cytometry-through intracellular detection of gamma interferon (IFN-γ) or interleukin 4 (IL-4) and CD69 expression- in 27 sustained virological responders (SVR): 13 with and 14 without occult HCV infection in PBMCs, detected by strand-specific real-time PCR. Ten healthy individuals and 14 chronically infected patients with viraemia, were included as controls.SVR without occult infection showed a higher percentage of activated CD4+ cells against peptides belonging to NS3 (p124, p153) and NS5b (p257, p294), activated CD8+ cells against NS3 (p124, p153, p158) and NS5b-p294, as well as an elevated percentage of CD4+ cells releasing IFN-γ + IL-4 against NS3-p153, and by CD8+ cells against NS3 (p124, p153). SVR without occult infection showed a higher percentage of activation and release of IFN-γ + IL-4 by both cell subpopulations than the two group of controls, in contrast to SVR with occult infection.The lower HCV-specific T-cell response found in SVR with occult infection indicates that the immune response may be impaired when the virus persists in PBMCs.