The frequency of PD-1−Tim-3− HCV-specific CTLs greatly outnumbered PD-1+Tim-3+ CTLs in patients with acute resolving infection. Moreover, the population of PD-1+Tim-3+ T cells was enriched for within the central memory T cell subset and within the liver. Blockade of either PD-1 or Tim-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes Buparlisib was increased exclusively by Tim-3 blockade. These results indicate that the coexpression of these inhibitory molecules tracks with defective T cell responses and that anatomical differences might account

for lack of immune control of persistent pathogens, which suggests their manipulation may represent

a rational target for novel immunotherapeutic approaches. Infection with the hepatitis C virus (HCV) results in viral persistence in the majority of infected individuals. Although the mechanisms of control of viral replication have not been fully determined, it is clear that the HCV-specific cellular immune response plays an indispensible role in viral clearance in the minority of individuals who spontaneously resolve infection.1 However, somewhat paradoxically, relatively broad HCV-specific T cell responses, which are often localized to the liver, may be detected in chronically infected individuals, even after many years of viremia. It buy XAV-939 is thus apparent that subversion of the adaptive cellular immune response by HCV plays an important role in persistent infection. A number of mechanisms are likely to contribute to ongoing HCV replication in the presence of an enduring HCV-specific cellular immune response. As an

RNA virus, HCV is highly mutable, allowing the phenomenon of cytotoxic T lymphocyte (CTL) “escape mutations” to occur: selection pressures exerted by HCV-specific CD8 T cells confer replicative advantages on viral subpopulations in which the genome encodes mutations that impair 4��8C presentation or recognition of epitopes. Such viral evolution in the chronically infected host leads the dominant viral species present to be poorly recognized by the HCV-specific CTL responses that have shaped viral mutation.2 However, although this mechanism may play a role in viral persistence and could explain the ongoing presence of some virus-specific T cell populations in the setting of active viral replication, available data indicates that a significant proportion of persisting CD8 T cells in chronically infected individuals may recognize epitopes that remain unmutated.3 Thus, mechanisms other than simple failure to recognize the ongoing presence of infecting virus due to mutational escape must underlie the inability of these virus-specific T cell populations to mediate viral clearance.