Antiviral mechanisms by which natural killer (NK) cells control murine cytomegalovirus (MCMV) infection in the spleens and livers of C57BL/6 mice were measured, revealing different mechanisms of control in different organs. Three days postinfection, MCMV titers in the spleens of perforin 0/0 mice were higher than in those of perforin ؉/؉ mice, but no elevation of liver titers was found in perforin 0/0 mice. NK cell depletion in MCMV-infected perforin 0/0 mice resulted only in an increase in liver viral titers and not in spleen titers. Depletion of gamma interferon (IFN-␥) in C57BL/6 mice by injections with monoclonal antibodies to IFN-␥ resulted in an increase of viral titers in the liver but not in the spleen. Analyses using IFN-␥-receptor-deficient mice, rendered chimeric with C57BL/6 bone marrow cells, indicated that in a recipient environment where IFN-␥ cannot exert its effects, the depletion of NK cells caused an increase in MCMV titers in the spleens but had little effect in the liver. IFN-␥ has the ability to induce a variety of cells to produce nitric oxide, and administrating the nitric oxide synthase inhibitor N-monomethyl-L-arginine into MCMV-infected C57BL/6 mice resulted in MCMV titer increases in the liver but not in the spleen. Taken together, these data suggest that in C57BL/6 mice, there is a dichotomy in the mechanisms utilized by NK cells in the regulation of MCMV in different organs. In the spleen NK cells exert their effects in a perforin-dependent manner, suggesting a cytotoxic mechanism, while in the liver the production of IFN-␥ by NK cells may be a predominant mechanism in the regulation of MCMV synthesis. These results may explain why the Cmv-1 r locus, which maps closely to genes regulating NK cell cytotoxic function, confers an NK cell-dependent resistance to MCMV infection in the spleen but not in the liver.
GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including in vitro antiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC 50 s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC 50 ؍ 316 nM). Additive to synergistic in vitro antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were ϳ40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of in vitro cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.T he NS3 serine protease of hepatitis C virus (HCV), which liberates essential nonstructural proteins from the HCV polyprotein, is required for viral replication (1) and may promote infection by blunting host innate immunity (2). Inhibitors of the HCV NS3/4A serine protease can induce rapid and substantial reductions in viral load. The NS3 protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are separately indicated for use in triple therapy combinations with pegylated alpha interferon (PEG-IFN) and ribavirin (RBV) for treating chronic genotype 1 (GT1) HCV infection. When added to PEG-IFN and RBV, telaprevir and boceprevir independently have increased rates of sustained virologic response (SVR) in GT1 HCV-infected patients (3-13). However, the standard of care still has many limitations, including a complex treatment regimen, significant drug-drug interaction potential, and adverse effects that can limit tolerability.There is continued need for novel NS3 protease inhibitors that are well tolerated, have minimal potential for drug-drug interactions, and provide more favorable treatment regimens to improve compliance. GS-9451 is a novel acyclic HCV protease inhibitor being developed for the treatment of GT1 HCV infection. GS-9451 inhibits NS3 protease by binding the active site of the enzyme in a reve...
The nonclinical safety profile of GS-8873, an HBV RNA transcript inhibitor was evaluated in rat and monkey 13-week toxicity studies with 8-week recovery phases. Vehicle or GS-8873 was dosed orally for 13 weeks at 2, 6, 20, and 60 mg/kg/day to Wistar Han rats and at 0.5, 1.5, 3 and 6 mg/kg/day to cynomolgus monkeys. In vitro and in vivo screening results from an analog discovered prior to GS-8873 informed the 13-week toxicology study designs. Neuroelectrophysiology and neurobehavioral evaluations were included at week 4 and 13 of the dosing and recovery phases for GS-8873. No adverse neurobehavioral effects were observed. Significant nerve conduction velocity (NCV) decreases and latency increases occurred at the high doses after 4 weeks of dosing. By week 13, dose responsive NCV reductions and latency increases worsened across all dose groups compared to controls. Some reversal occurred 8 weeks after the last dose administered, but not to vehicle control levels. A minimal, axonal degeneration was observed in rat spinal and peripheral nerves across dose groups compared to controls. No monkey nervous system microscopic findings were observed. NOAELs could not be determined for either species due to the neuroelectrophysiology findings and development was halted in the interest of safety. A retrospective risk assessment approach utilizing benchmark dose (BMD) modeling contributed 13-week NCV BMDL estimates (lower limits of the 95% confidence interval) in lieu of NOAELs. The best fitted models extrapolated NCV BMDLs for the rat caudal and monkey sural nerve at 0.3 mg/kg/day and 0.1 mg/kg/day, respectively.
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