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Differential behavior of the Mo + PyF101 enhancer variant of Moloney murine leukemia virus in rats and mice
B K Brightman1, M Okimoto, V Kulkarni
1Department of Molecular Biology and Biochemistry, University of California, Irvine 92697-3900, USA.
Abstract:
The Mo + PyF101 enhancer variant of Moloney murine leukemia virus (M-MuLV) has been very useful in investigating M-MuLV leukemogenesis. When inoculated subcutaneously (s.c.) into neonatal mice, Mo + PyF101 M-MuLV is attenuated for development of disease. Previous studies in mice infected with wild-type M-MuLV have revealed several important preleukemic events, including development of splenic hyperplasia, defects in bone marrow hematopoiesis, and in vivo generation of MCF viruses that arise by recombination in the uninfected mouse. Mo + PyF101 M-MuLV is defective in inducing these effects after s.c. inoculation. In the experiments reported here, a study of Mo + PyF101 M-MuLV infection in rats was carried out. Wild-type M-MuLV is leukemogenic in rats, but infected rats do not form MCF recombinants since they lack the necessary endogenous polytropic envelope sequences. Since Mo + PyF101 M-MuLV's leukemogenic defect is correlated with a failure to generate MCF recombinants, it seemed possible that wild-type M-MuLV might not have a leukemogenic advantage over Mo + PyF101 M-MuLV in rats, where MCF recombinants cannot form. Neonatal Fisher F344 rats were inoculated s.c. or intraperitoneally by wild-type and Mo + PyF101 M-MuLVs. Surprisingly, Mo + PyF101 M-MuLV was completely deficient in leukemogenesis in rats when inoculated by either route while wild-type M-MuLV induced lymphoma with the predicted time course. The leukemogenic defect for Mo + PyF101 M-MuLV resulted from a pronounced defect for establishing infection in rats. Further studies of wild-type M-MuLV in rats indicated that infection was confined almost exclusively to the thymus at early times. In mice wild-type M-MuLV establishes substantial infection in other hematopoietic organs such as spleen and bone marrow as well. Thymic infection was also correlated with a decrease in thymic cellularity at early times.
Insights
The Mo + PyF101 enhancer variant of Moloney murine leukemia virus (M-MuLV) showed a complete deficiency in causing leukemia in rats, unlike wild-type M-MuLV. This defect is due to an inability to establish infection in rats, primarily affecting thymic cellularity.
Area of Science:
- Virology
- Oncology
- Immunology
Background:
- Moloney murine leukemia virus (M-MuLV) is a retrovirus extensively studied for its role in leukemogenesis.
- The Mo + PyF101 enhancer variant of M-MuLV is attenuated in mice, showing fewer preleukemic events compared to wild-type M-MuLV.
- Wild-type M-MuLV is leukemogenic in rats, but rats do not generate MCF recombinant viruses due to a lack of necessary endogenous sequences.
Purpose of the Study:
- To investigate the leukemogenic potential of Mo + PyF101 M-MuLV in rats, comparing it to wild-type M-MuLV.
- To determine if the absence of MCF recombinant virus generation in rats affects the leukemogenic advantage of wild-type M-MuLV.
- To elucidate the mechanisms underlying M-MuLV infection and leukemogenesis in rats.
Main Methods:
- Neonatal Fisher F344 rats were inoculated with either wild-type M-MuLV or Mo + PyF101 M-MuLV via subcutaneous or intraperitoneal routes.
- Leukemogenesis was monitored over time, with a focus on lymphoma development.
- Infection patterns in hematopoietic organs, particularly the thymus, spleen, and bone marrow, were analyzed in infected rats.
Main Results:
- Mo + PyF101 M-MuLV was completely deficient in inducing leukemia in rats, regardless of the inoculation route.
- Wild-type M-MuLV induced lymphoma in rats with a typical time course.
- The leukemogenic defect of Mo + PyF101 M-MuLV was attributed to a significant failure in establishing infection in rats.
- In wild-type M-MuLV-infected rats, viral infection was predominantly localized to the thymus early on, leading to decreased thymic cellularity.
Conclusions:
- The Mo + PyF101 enhancer variant of M-MuLV is not leukemogenic in rats due to a profound defect in establishing infection.
- Unlike in mice, the generation of MCF recombinant viruses is not a factor in the leukemogenic potential of M-MuLV in rats.
- Early thymic infection by wild-type M-MuLV in rats is a critical event associated with leukemogenesis and thymic pathology.