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Antiviral treatment with WIN 54 954 reduces mortality in murine coxsackievirus B3 myocarditis
J Fohlman1, K Pauksen, T Hyypiä
1Department of Infectious Diseases, University Hospital, Uppsala, Sweden.
Insights
Early administration of WIN 54 954 significantly improves survival in Coxsackievirus B (CBV)-induced myocarditis by inhibiting viral replication without compromising immunity.
Area of Science:
- Virology
- Immunology
- Cardiology
Background:
- Coxsackieviruses B (CBVs) are primary causes of myocarditis.
- CBVs are linked to dilated cardiomyopathy, a condition with low survival rates without transplantation.
Purpose of the Study:
- To evaluate the efficacy of the antiviral agent WIN 54 954 against CBV-induced myocarditis.
- To assess the impact of WIN 54 954 on viral replication, inflammation, and immune response.
Main Methods:
- In vitro testing of WIN 54 954 against CBV3 replication.
- In vivo administration of WIN 54 954 to infected A/J mice.
- Analysis of mortality, myocardial inflammation, lymphocyte markers, and antibody titers.
Main Results:
- WIN 54 954 inhibited CBV3 replication in vitro (MIC = 0.02 mg/L).
- Early WIN 54 954 treatment (100 mg/kg BID PO) provided complete protection from mortality (P < .01).
- Treatment did not alter myocardial inflammation, lymphocyte markers, or CBV3 antibody titers, suggesting intact immunity.
Conclusions:
- WIN 54 954 is a potent antiviral agent effective against CBV-induced myocarditis in mice when treatment is initiated early.
- The survival benefit is attributed to inhibition of viral replication, not immune modulation.
- WIN 54 954 shows promise for treating enteroviral myocarditis.
Background:
Coxsackieviruses B (CBVs) are dominant causative agents in myocarditis and are associated with pathogenesis is some cases of dilated cardiomyopathy, a clinical entity with a poor survival without heart transplantation.
Methods And Results:
In vitro, the antiviral agent WIN 54 954 was shown to inhibit replication of CBV3 at a minimal inhibitory concentration value of 0.02 mg/L. Administration of WIN 54 954, 100 mg/kg BID PO, beginning on the day of infection resulted in complete protection from enteroviral mortality (P < .01). WIN 54 954 treatment did not abrogate the inflammatory reaction in the myocardium. No difference was found in the expression of surface lymphocyte subset markers. At 3 weeks, macrophages seemed to dominate the inflammatory reaction, regardless of treatment. There was no difference in CBV3 antibody titers, indicating that WIN 54 954 does not interfere with the development of protective immunity. Complement factors C3 and B were synthesized at a higher level during infection and correlated well with the degree of inflammatory reaction.
Conclusions:
The results show that WIN 54 954 is a potent antiviral agent with a highly significant effect on survival in CBV-induced myocarditis in the A/J mouse if treatment is started early. It is suggested that the reduction in mortality seen with WIN 54 954 administration is due to an inhibitory effect on virus replication in affected organs that does not interfere with cellular or humoral immunity.