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Effect of 3'azidothymidine administered in drinking water or by continuous infusion on the development of MAIDS
J L Eiseman1, R A Yetter, T N Fredrickson
1University of Maryland Cancer Center, University of Maryland School of Medicine, Baltimore 21201.
Abstract:
LP-BM5 MuLV infection of C57BL/6 mice induces a well characterized, lymphoproliferative, immunodeficiency disease (MAIDS), which is useful for evaluation of potential antiviral agents, because of the reproducibility of virological and clinical endpoints. This MAIDS retrovirus model was used to evaluate 3'azido-2,3'dideoxythymidine (AZT), using different doses, methods of administration and timing for initiation and continuation of therapy. AZT therapy 1 mg/ml in the drinking water given 30 days prior to virus challenge, and continued for 16 weeks, prevented LP-BM5 MuLV dissemination and disease in 13 of 15 treated mice. Efficacy was dose dependent for AZT concentrations of 1, 0.5, and 0.1 mg/ml in drinking water. One mg/ml AZT was most effective in preventing infection if therapy was begun within days prior to virus challenge or within the first four hours after virus inoculation. If treatment was initiated later, disease was delayed. Continuous infusion of AZT, 25 micrograms/h, was effective since virus was not detected in spleens of any mice during the 21 days of AZT treatment. However, after treatment was stopped treated mice became virus positive and disease progressed. Likewise, AZT administration at 1 mg/ml in the drinking water for only 21 days post virus inoculation (p.i.), was not sufficient to prevent virus dissemination or disease.
Insights
Zidovudine (AZT) effectively prevents and treats murine acquired immunodeficiency syndrome (MAIDS) in mice when administered early and continuously. Early and sustained AZT treatment is crucial for long-term efficacy against retroviral infections.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Murine acquired immunodeficiency syndrome (MAIDS) is induced by LP-BM5 MuLV infection in C57BL/6 mice.
- This model offers reproducible virological and clinical endpoints for evaluating antiviral agents.
Purpose of the Study:
- To evaluate the efficacy of 3'azido-2,3'dideoxythymidine (AZT) in the MAIDS retrovirus model.
- To determine the impact of different doses, administration methods, and treatment timing on AZT's effectiveness.
Main Methods:
- Mice were treated with varying doses of AZT via drinking water or continuous infusion.
- Treatment initiation and continuation were varied relative to LP-BM5 MuLV challenge.
- Viral dissemination and disease progression were monitored in treated and control groups.
Main Results:
- Continuous AZT therapy (1 mg/ml in drinking water for 16 weeks) prevented LP-BM5 MuLV dissemination and disease in most mice.
- Efficacy was dose-dependent, with higher AZT concentrations showing greater effectiveness.
- Early treatment initiation (pre-challenge or within 4 hours post-inoculation) was most effective; later treatment only delayed disease.
- Continuous infusion of AZT was effective during treatment, but disease progressed upon cessation.
- Short-term (21 days) AZT administration was insufficient to prevent long-term viral spread or disease.
Conclusions:
- AZT demonstrates significant potential as an antiviral agent against MAIDS.
- Optimal efficacy of AZT requires early initiation and sustained administration.
- The timing and duration of AZT therapy are critical factors in controlling retroviral infection and disease progression.