Both forms of MAVS, FL and cleaved, were detected in liver biopsy specimens from patients with CHC, whereas only FL MAVS was detected in controls (Fig. 1A, B). For all analyses, signal intensities of FL and cleaved MAVS were normalized to β-actin. The percentage of MAVS cleavage (cleaved/total MAVS × 100) varied widely among the

129 CHC patients, ranging from 0 to 76% (mean, 18%; standard deviation 21%) (Fig. 1B). Cleavage of MAVS was detected in 62 of the 129 patients (48%), and the percentage of cleavage in these 62 patients showed a normal distribution ranging from 7% to 76% (mean, 37%; standard deviation 16%). Only FL MAVS was detected in the remaining 67 patients. Because only the FL form of MAVS is functional, and because it is Quizartinib concentration unknown whether and how fast the cleaved MAVS product is degraded in Sotrastaurin price cells, we also performed all our analyses using the FL MAVS/beta-actin signal intensity ratio. The amount of FL MAVS showed strong negative correlation with the percentage of cleaved MAVS (Spearman r =-0.57, P < 0.0001; data not shown). There was a wide variation in the amount of functional FL MAVS within both the CHC and control patient groups (Fig. 1C), with the

median value being significantly lower in CHC compared with control samples (0.48 versus 0.77; P = 0.0007). Immunoblotting with the polyclonal MAVS antiserum AT107 yielded results similar to those obtained with mAb IID12 (Adri 1) (data not shown). We conclude that HCV-induced cleavage of MAVS reduces the amount of the functional FL MAVS in a considerable proportion of patients with CHC. Cleavage of MAVS was independent from the Metavir activity grade or fibrosis score (data not shown). All investigated HCV GTs were able to cleave MAVS. Samples from patients infected with the easier-to-treat GTs 2 or 3 had significantly lower

amounts of FL MAVS compared with the difficult-to-treat GTs 1 and 4 (P = 0.009; Fig. 1D). There was no significant difference between GT 2/3 and GT 1/4 patients with respect to viral load (VL), Metavir activity grade, or fibrosis score. Therefore, the difference most likely reflects different intrinsic properties of HCV GTs with respect to MAVS cleavage. Because in vitro studies demonstrated a very click here efficient cleavage of MAVS by the HCV NS3-4A protease,8, 16, 20 we assessed whether patients with a high VL show more MAVS cleavage in the liver. Indeed, there was a weak but statistically significant inverse correlation between the amount of FL MAVS and serum VL (Spearman r =-0.22, P = 0.011; Fig. 2A) and a strong positive correlation between the percentage of cleaved MAVS and serum VL (Spearman r = 0.53, P < 0.0001; Fig. 2B). The correlation remained significant when only the 62 samples with some detectable degree of MAVS cleavage were included in the analysis (Fig. 2C).