Impairment of IFN production is observed for both NK cells and T cells, but induced by different mechanisms. opportunity to study the reversibility of the suppressed cytokine production of NK cells in comparison with the antigen-induced defect in IFN and tumor necrosis factor- production of virus-specific T cells. This has implications for immune reconstitution in other conditions of chronic inflammation and?immune exhaustion, such as human immunodeficiency virus infection and cancer. patients who are homozygous for alleles as compared with patients who are homozygous or heterozygous for alleles. and represent two groups of alleles that differ in two amino acids in their respective HLA-Cw 1 domains. Because the conversation between KIRs on NK cells with HLA molecules on target cells plays a key role in NK cell inhibition, it has been suggested that this compound genotype results in a lower activation threshold of NK cells, thereby allowing faster NK cell activation compared with less favorable genotypes. This is supported by data in an in?vitro influenza A virus contamination model that demonstrate a larger HLA-CCregulated NK cell subset with more rapid NK cell IFN- secretion and cytotoxicity in than in homozygous patients.22 An increased prevalence of homozygosity is also observed in injection drug users who remain aviremic and antibody-negative despite high-risk behavior and frequent HCV exposure.21 The apparent immune protection in such individuals is associated with KIR2DL3 expression on NK cells23 and with an increased frequency of activated NK cells.24, 25 At the functional level, NK cells in the blood of exposed uninfected individuals display increased ex?vivo IFN production24 and increased in?vitro cytotoxicity.25 These results from cross-sectional cohorts ARN-3236 are consistent with data from a prospective study of health care workers observed after an accidental needlestick.26 Accidental exposure to minute amounts Rabbit Polyclonal to EPHA3 of HCV-containing blood resulted in a transient increase the frequency of activated NK cells in the blood and their effector functions (both cytotoxicity and IFN production). The magnitude of the NK cell response correlated with that of the subsequent HCV-specific T-cell response. This likely represents an early innate response to an abortive or rapidly contained and cleared contamination, because neither viremia nor HCV-specific antibodies are detected.26 Collectively, these studies demonstrate that NK cells are sensitive biomarkers of subclinical HCV exposure. While it is possible that NK cellsalong with other components ARN-3236 of the innate immune systemcontribute to viral containment in this setting, it is obvious that innate immune responses on their own cannot clear the infection once high-level HCV viremia is established. Data from prospectively studied humans and experimentally infected chimpanzees demonstrate that high-level HCV viremia persists for weeks despite induction of a large set of intrahepatic interferon-stimulated genes ARN-3236 (and set that includes many antiviral and proinflammatory genes.30 However, owing to HCVs elaborate strategies to escape from IFN responses,29, 31 there is no decrease in viremia, just a plateau. Patients are typically clinically asymptomatic during this period and do not seek medical attention. The onset of clinically symptomatic acute hepatitis with increased alanine aminotransferase levels occurs 8 to 10?weeks after contamination. Without treatment, two-thirds of the infected patients develop chronic hepatitis C, which is usually associated ARN-3236 with a 2C3 log10 reduction in viral titer. Because liver biopsies are clinically not indicated in the acute phase of hepatitis C, the intrahepatic effector responses responsible for the decrease in viremia have not been studied in patients. However, data from biopsy tissues of experimentally infected chimpanzees have clearly shown that this decrease in viremia coincides with an increase in intrahepatic IFN-mRNA levels.27, 28, 32 The relative contribution of T cells and NK cells to IFN production and antiviral response is not known at this time. Whereas the appearance and maintenance of HCV-specific T-cell responses in the blood, in particular CD4 T-cell proliferation and cytokine production, are the best predictors of viral clearance,32, 33, 34, 35, 36, 37 NK cells are also activated and display increased cytotoxicity and IFN production.38, 39, 40 Pelletier et?al39 recently reported a correlation between the magnitude of.