Nitric oxide and chronic HCV and HIV infections

High concentrations of nitric oxide (NO) are generated by the inducible for m of the enzyme nitric oxide synthase (iNOS), which is expressed in activat ed macrophages and in hepatocytes. Increased expression of iNOS in hepatocy tes or macrophages might be expected in chronic HCV liver disease and HIV i nfections. This might in turn be reflected in increased serum NO levels in these two conditions. In view of the discrepant findings in published repor ts, we measured serum NO levels in a large number of chronic HCV-infected p atients and patients with chronic HIV infections with or without AIDS-relat ed opportunistic infection. We also localized HCV and iNOS antigens by immu nohistochemistry, in liver biopsy tissue from patients with chronic HCV-rel ated hepatitis, HCV-related cirrhosis, and HCV-related hepatocellular carci noma. A group of 121 subjects with serological evidence of I-ICV with or wi thout HIV infection were studied. These were compared with 14 controls with out HIV or HCV disease (group A). Among the subjects with HCV, 35 were nega tive for HIV (group B), 66 were HIV positive (group C), and 20 had AIDS-rel ated opportunistic infection (group D). The serum NO concentration was dete rmined by the Brucine method. A well-characterized commercially available a ntibody (HCV88) directed against a synthetic NS3 peptide fragment of HCV, w hich localizes to the hepatocyte nuclei, and an antibody to human macrophag e iNOS, were both used to detect these proteins in liver biopsy tissue by i mmunohistochemistry. Mean serum NO values in HIV negative/HCV negative cont rol patients (group A) (54.6 +/- 12 muM) were similar to those in HIV negat ive/HCV positive patients (group B) (55.0 +/- 13 muM and HIV positive witho ut AIDS-related disease/HCV positive patients (group C) (47.2 +/- 25 muM). By contrast, the mean serum NO (70.1 +/- 24 muM) was significantly increase d in HCV-positive patients with AIDS-related infection (group D) compared t o controls (P = 0.02). HCV NS3 and iNOS antibody staining hepatocytes were not detected in any of the control non-HCV-infected biopsy samples. In earl y chronic HCV hepatitis (fibrosis scores F0-F2), HCV NS3 antigen localized focally to only a small number of hepatocytes. In cirrhosis (fibrosis score F4) with or without hepatocellular carcinoma, the majority of hepatocyte n uclei stained positively with HCV NS3 antibody. The majority of hepatocytes in chronic HCV hepatitis expressed iNOS, irrespective of histological dise ase severity. The staining was present uniformly in the cytoplasm. In chron ic HCV and HIV coinfection, the pattern and number of iNOS staining cells w ere similar to that in patients with chronic HCV infection alone. In conclu sion, there is widespread expression of iNOS in hepatocytes in chronic HCV liver disease, irrespective of liver disease stage. However, elevated NO le vels in serum were related only to active AIDS-related bacterial, protozoan , and fungal infections, rather than to chronic viral infection with HCV or HIV alone. NO may play a role in the local control of chronic viral infect ions at tissue level, but this is not reflected in serum levels.