It was reported not only in patients with cryptogenic liver disease [35] but also in hemodialysis patients Wortmannin msds [36]. Since a previous study reported HCV-specific T cell responses in occult HCV infection [15], we attempted to detect occult HCV infection in seronegative, aviremic patients with HCV-specific cellular immune responses. We performed secondary nested RT-PCR of PBMC samples in all of the hemodialysis patients and obtained a positive result in three seronegative, aviremic patients as well as in all five of the patients positive for HCV RNA by clinical-grade RT-PCR (COBAS TaqMan HCV assay, Roche Diagnostics) (Table 2). However, the three patients with occult HCV infection were not among the eight patients who displayed HCV-specific T cell responses.

All eight of the patients with HCV-specific T cell responses showed no sign of occult HCV infection by nested PCR. Thus, occult HCV infection was not a cause of the HCV-specific T cell responses in seronegative, aviremic patients. Table 2 Hemodialysis patients with secondary nested RT-PCR (+). Next, heterologous T cell immunity by a cross-reactive epitope was considered as a possible cause of the T cell responses seen in seronegative, aviremic patients. As shown in Table 1, however, T cells from a single patient were specific for multiple HCV epitopes. At least two epitopes were recognized by T cells from each patient, with exception of one, CMI-4 (Table 1). This finding suggested prior T cell priming by bona fide HCV proteins, and not by cross-reactive epitopes from other pathogens.

In addition, the identified epitope peptides did not show any significant homology in amino acid sequence with peptides from other known pathogens by NCBI database searches. Of interest, T cell epitopes were found not only in structural proteins but also in non-structural (NS) proteins (Figure 1B and Table 1). T cell responses to HCV NS proteins are evidence of de novo synthesis of viral proteins in the host. Therefore, we concluded that the HCV-specific T cell responses observed in seronegative, aviremic patients resulted from prior exposure to HCV, even though there was no serological or clinical-grade RT-PCR evidence of current or past HCV infection. Comparison of different groups of patients in clinical aspects In the present study, we identified different groups of hemodialysis patients according to HCV infection and immune status. There were chronic HCV-infected group (seropositive and viremic in clinical-grade RT-PCR) and occult HCV-infected group (seronegative and aviremic, but positive in nested RT-PCR). In addition, there were polyfunctional T cell responder group, TNF-��-predominant T cell responder group and non-responder group Batimastat in seronegative, aviremic patients.