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Prevention of murine AIDS development by (R)-9-(2-phosphonylmethoxypropyl)adenine
1Center for Chronic Viral Diseases, First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Japan.
Abstract:
LP-BM5 murine leukemia virus (MuLV) infection causes severe immunodeficiency termed murine AIDS (MAIDS). The acyclic nucleoside phosphonates, (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) were examined, in comparison with zidovudine (AZT), for their inhibitory effect on the development of MAIDS. Although no significant difference in inhibition of LP-BM5 MuLV replication was identified between PMPA and PMEA in cell cultures, PMPA was obviously less cytotoxic to the host lymphocytes. None of the mice treated in vivo with 5 or 25 mg/kg of PMPA or 25 mg/kg of PMEA developed MAIDS at 5 weeks after viral infection. However at 9 weeks, none of the 25 mg/kg PMPA-treated mice progressed to MAIDS, except for one that developed mild MAIDS, whereas PMEA, even at 100 mg/kg, could not prevent disease progression. MAIDS-associated activation of lymphocytes and viral replication were drastically inhibited by PMPA treatment. These results indicate that PMPA is a highly effective antiretroviral agent in vivo.
Insights
The antiviral drug PMPA effectively prevents the development of murine AIDS (MAIDS) in mice infected with LP-BM5 murine leukemia virus (MuLV). PMPA demonstrated superior efficacy and reduced toxicity compared to PMEA and AZT in this in vivo study.
Area of Science:
- Virology
- Immunology
- Antiviral Research
Background:
- LP-BM5 murine leukemia virus (MuLV) infection induces severe immunodeficiency in mice, known as murine AIDS (MAIDS).
- Existing antiretroviral agents have varying efficacy and toxicity profiles in managing retroviral infections.
Purpose of the Study:
- To evaluate the efficacy of acyclic nucleoside phosphonates, PMPA and PMEA, in preventing MAIDS development.
- To compare the in vivo antiretroviral activity and host toxicity of PMPA and PMEA against zidovudine (AZT).
Main Methods:
- In vitro assessment of LP-BM5 MuLV replication inhibition and cytotoxicity of PMPA and PMEA.
- In vivo administration of PMPA and PMEA to mice post-LP-BM5 MuLV infection.
- Monitoring of MAIDS development, lymphocyte activation, and viral replication at 5 and 9 weeks.
Main Results:
- PMPA and PMEA showed similar inhibition of MuLV replication in vitro, but PMPA exhibited lower cytotoxicity.
- In vivo, PMPA (25 mg/kg) significantly prevented MAIDS progression at 9 weeks, with only one mild case observed.
- PMEA, even at higher doses, failed to prevent MAIDS progression, and PMPA treatment drastically inhibited MAIDS-associated lymphocyte activation and viral replication.
Conclusions:
- PMPA is a highly effective antiretroviral agent in vivo for preventing MAIDS.
- PMPA demonstrates superior efficacy and reduced host toxicity compared to PMEA in the context of MAIDS.
- These findings support PMPA as a promising therapeutic candidate for retroviral infections.