Occult hepatitis C virus (HCV) infection is a type of recently identified chronic infection that is evidenced only by detection of HCV RNA in liver; patients consistently test negative for antibodies to HCV and HCV RNA in serum. Using ex vivo and in vitro measures of T-cell responses, we have identified functional virus-specific memory CD4؉ and CD8 ؉ T cells in the peripheral blood of patients with occult HCV infection. The features of the virus-specific T cells were consistent with immune surveillance functions, supporting previous exposure to HCV. In addition, the magnitudes of CD4؉ and CD8 ؉ T-cell responses were in parallel and correlated inversely with the extent of liver HCV infection. The detection of HCV-specific T cells in individuals in whom HCV RNA can persist in the liver despite the absence of viremia and antibodies indicates that HCV replication is prolonged in the face of virus-specific CD4؉ and CD8 ؉ T-cell responses. These findings demonstrate that HCV-specific cellular immune responses are markers not only of previous exposure to and recovery from HCV but also of ongoing occult HCV infection.Current criteria for hepatitis C virus (HCV) infection include detection of specific antibodies by enzyme immunoassay and confirmation by immunoblot assay (40). Chronic HCV infection is established in approximately 50 to 80% of virusexposed individuals, with 170 million people being infected worldwide (30). Patients in whom HCV persists usually remain positive for anti-HCV and HCV RNA in serum unless HCV is cleared from the circulation either spontaneously or under antiviral treatment (30,41). Another type of chronic infection, occult HCV, has recently been identified in a group of patients who have abnormal liver function tests and histological damage (2). Occult HCV infection is characterized by the presence of HCV RNA in the liver in patients who consistently test negative for antibodies to HCV and HCV RNA in serum. Compared with chronic hepatitis C, occult HCV infection seems to be a less aggressive form of the disease caused by the hepatitis C virus (25). A recent report suggests that interferonbased therapy may have potential benefits in the treatment of patients with occult HCV infection (24).Virus-specific T-cell responses have been detected in the blood of HCV-seronegative healthy persons frequently exposed to HCV (16,36) and in patients lacking humoral responses who have presumably recovered from acute hepatitis C (41). HCV-specific cellular responses can be detected in patients receiving antiviral therapy in association with HCV RNA clearance from the blood (5,11,12). In spite of this, detectable HCV may persist in the liver in so-called sustained responders to treatment (27,29). Therefore, we questioned whether HCV-specific T-cell responses are detectable in patients with occult HCV infection.(This work was presented in part at the 55th Annual Meet- MATERIALS AND METHODSStudy subjects. Fifty patients with occult HCV infection were enrolled in this study. The selection criteria were having susta...

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Hepatitis C virus (HCV) RNA persistence in the liver has been described even after apparent resolution of HCV infection. Because T-cell reactivity plays a role in recovery from HCV infection, virus-specific T-cell responses were investigated in apparently recovered individuals in whom hepatic HCV RNA persistence was documented: 15 sustained virological responders to interferon (IFN)-treatment and 9 asymptomatic aviremic anti-HCV carriers. HCV-specific CD4(+) T-cell proliferative responses were detected significantly more often in apparently recovered individuals (sustained virological responders: 60%; asymptomatic anti-HCV carriers: 66%) compared with 50 chronic hepatitis C patients (28%; P < 0.05). However, T-cell frequencies and numbers tended to decline over time and the number of HCV proteins targeted by CD4(+) T-cell proliferative responses was limited. Interestingly, liver viral load correlated inversely with virus-specific immune responses. Thus, CD4(+) T-cell responders showed significantly lower hepatic HCV RNA levels (P < 0.05). HCV-specific IFN-gamma-secreting CD4(+) T-cells were not detected in all the apparently recovered patients although they were found significantly more often compared with chronic hepatitis C patients (P < 0.05). Also, HCV NS3-specific CD8(+) T-cells were detected in 11 HLA-A2-positive apparently recovered individuals (8 sustained virological responders and 3 asymptomatic anti-HCV carriers); T-cell frequencies tended to be greater in those patients who had lower hepatic viral levels. In conclusion, HCV-specific T-cells are detectable in apparently recovered individuals in whom HCV RNA can persist in the liver indicating that HCV replication may be prolonged in the face of an insufficient or inadequate virus-specific CD4(+) and CD8(+) T-cell response.

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