, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-␥-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-␣ stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-␣ receptor expression, though IFN-␣ receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-␣-induced NK cell activity and not to altered IFN-␣ receptor, NKP30, NKP44, NKP46, or NKG2D expression.Immature dendritic cells (DC) are key innate mediators of the adaptive immune response. Myeloid DC (MDC) and plasmacytoid DC (PDC) have been identified as two main peripheral DC subsets (43). Numerical and functional defects in these populations have been described for both hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections, with the impairments distinctly different in each infection (3,12,19,26,33,48,53,56,57). Natural killer (NK) cells are capable of cytotoxic, cytokine-expressing, and chemokine-expressing functions (31, 38). These lymphocytes are vital during the early stages of mouse hepatic viral infection (22, 42) and during human herpes virus infection (5, 7, 10). NK cell cytotoxic function has long been known to be reduced during chronic HIV infection and in subjects with AIDS (32, 44), and unfractionated cell assays of NK cell function indicate an impaired NK cell response to alpha interferon (IFN-␣) (52). Additionally, genetic markers of NK cell phenotype are associated with disease progression rate (36). In contrast, HIVexposed but uninfected subjects appear to have enhanced NK cell function (45), and after highly active antiretroviral therapy (HAART), NK cell numbers and function appear to normalize (1, 4). In the setting of HCV infection, genetic markers of NK cell phenotype appear to predict the outcome after acute exposure (28). During chronic HCV infection, some studies indicate reduced NK cell cytotoxicity (14, 40, 55), while morerecent studies indicate normal NK cell function and reduced peripheral NK cell numbers (18,27,39).DC-NK cell bidirectional cross talk has recently been shown to play a key role in host defense (20,30,34,35,37). This cross talk can be facilitated by Toll-like receptor (TLR) signaling and results in NK cell activation, enhanced NK cell effector function, and DC maturation (15,20,21,30,49). In the setting of viremic HIV infection, recent unfractionated cell system data indicate impairment in PDC-dependent NK cell activity (11). These data may be explained by the previously described numerical defects in PDC or NK cells, though whether there are additional functional defects ...