INHIBITORY EFFECT OF NITRIC-OXIDE ON THE REPLICATION OF A MURINE RETROVIRUS IN-VITRO AND IN-VIVO

Nitric oxide (NO) exerts microbicidal effects on a broad spectrum of p athogens, including viruses, but its antiretrovirus properties have no t yet been described. The purpose of this study was to determine wheth er NO inhibits murine Friend leukemia virus (FV) replication in vitro and to what extent NO may play a role in defenses against FV infection in mice, Three NO-generating compounds were studied: 3-morpholino-syd ononimine (SIN-1), sodium nitroprusside (SNP), and S-nitroso-N-acetylp enicillamine (SNAP). The effects of these three compounds were compare d with those of their controls (SIN-1C, potassium ferricyanide, and N- acetylpenicillamine, respectively), which do not generate NO and with that of sodium nitrite (NaNO2). SIN-1, SNP, and SNAP inhibited FV repl ication in dunni cells in a concentration-dependent manner. In contras t, no significant inhibitory effect was observed with the three contro ls or NaNO2. Furthermore, the addition of superoxide dismutase did not alter the inhibitory effect of SIN-1, which is also known to generate superoxide anions, No dunni cell toxicity was observed in the range o f concentrations tested. We also assessed the effect of NO produced by activated macrophages on FV replication, Macrophages activated by gam ma interferon and lipopolysaccharide inhibited FV replication in a con centration-dependent manner. This inhibition was due in part to NO pro duction, since it was reversed by N-G-monomethyl L-arginine, a competi tive inhibitor of NO synthase, In vivo administration of N-G-nitro-L-a rginine methyl ester, a competitive inhibitor of NO synthase, signific antly increased the viral load in spleen cells of FV-infected mice, Th ese results suggested that NO may play a role in defenses against the murine Friend leukemia retrovirus.