RESISTANCE TO MURINE HEPATITIS-VIRUS STRAIN-3 IS DEPENDENT ON PRODUCTION OF NITRIC-OXIDE

The strain-specific spectrum of liver disease following murine hepatit is virus type 3 (MHV-3) infection is dependent on inflammatory mediato rs released by macrophages. Production of nitric oxide (NO) by macroph ages has been implicated in resistance to a number of viruses, includi ng ectromelia virus, vaccinia virus, and herpes simplex virus type 1. This study was undertaken to define the role of NO in MHV-3 infection. Gamma interferon-induced production of NO inhibited growth of MHV-3 i n a murine macrophage cell line (RAW 264.7). Viral inhibitory activity was reproduced by the NO donor S-nitroso-N-acetyl-DL-penicillamine (S NAP), whereas N-acetyl-DL-pencillamine (NAP), an inactive analog of SN AP, had no effect. Electron microscopy studies confirmed the inhibitor y effects of NO on viral replication. Peritoneal macrophages isolated from A/J mice known to be resistant to MHV-3 produced a fivefold-highe r level of NO and higher levels of mRNA transcripts of inducible NO sy nthase in response to gamma interferon than macrophages from susceptib le BALB/cJ mice. SNAP inhibited growth of MHV-3 in macrophages from bo th strains of mice to similar degrees. In vivo inhibition of NO by N-m onomethyl-L-arginine resulted in loss of resistance to MHV-3 in A/J mi ce. These results collectively demonstrate a defect in the production of NO in macrophages from susceptible BALB/cJ mice and define the impo rtance of endogenous NO in resistance to MHV-3 infection in resistant A/J mice.