It remains possible that in our patients, www.selleckchem.com/products/kpt-330.html anti-HCV antibody was generated during an acute infection and has over the course of many years disappeared from circulation. In fact, a previous study demonstrated that anti-HCV disappeared 20 years after recovery from acute HCV infection while cellular immune responses persisted [21]. Clinical implications of HCV-specific T cell response in seronegative, aviremic persons will require further investigation. In addition, phenotypic characteristics of HCV-specific T cells needs to be analyzed in further studies, including memory markers, activation markers and exhaustion markers. In the present study, we showed two distinct patterns of T cell polyfunctionality in seronegative, aviremic patients (Figures 3, ,4,4, and and5).5).

HCV-specific memory T cells were highly polyfunctional in some patients (group I in Figure 3), whereas they were TNF-��-predominant in the others (group II in Figure 3). Recently, T cell polyfunctionality has been investigated in HIV infection and vaccination studies [27]�C[29] and it was found that polyfunctional HIV-specific CD8+ T cells were maintained in HIV long-term nonprogressors [28]. Furthermore, in a Leishmania vaccination study, the degree of Th1 cell polyfunctionality was shown to correlate with vaccine efficacy [27]. In addition, the profound efficacy of the smallpox vaccine has been attributed to polyfunctionality of virus-specific CD8+ T cells. Taken together, polyfunctional HCV-specific memory T cells in seronegative, aviremic patients would be expected to protect against subsequent exposure to HCV.

Intriguingly, a very recent study demonstrated that polyfunctional HCV-specific T cells were associated with vaccine-induced control of HCV [41]. In patients with a TNF-��-predominant response, HCV-specific T cells might not provide antiviral protection upon subsequent HCV exposure. We can infer the absence of a protective role for TNF-��-single-positive T cells from a recent study of tuberculosis. In this study, TNF-��-single-positive Mycobacterium tuberculosis-specific CD4+ T cells were preferentially detected in active tuberculosis disease rather than in latent infection [42]. It is possible that TNF-��-single-positive T cell responses might serve solely as evidence of T cell priming by exposure to pathogen.

In the present study, we suggest that HCV-specific memory T cells of seronegative, aviremic patients might result from transient viral replication without seroconversion or, alternately, from disappearance of anti-HCV antibody Dacomitinib long after prior HCV infection. If these assumptions prove true, it would suggest that past HCV exposure may be better assessed by HCV-specific T cell responses than by presence of anti-HCV antibody. In fact, HCV-specific T cell assays could confirm HCV exposure in indeterminate blood donors [43]�C[45].