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Unique sequence and lesional tropism of a new variant of neuropathogenic friend murine leukemia virus
1Institute of Life Science, Soka University, Hachioji, Tokyo, Japan. takase@scc1.t.soka.ac.jp
Abstract:
FrC6 murine leukemia virus (MuLV) is a replication-competent, neuropathogenic variant derived from Friend MuLV (F-MuLV) complex. The A8 virus (a molecular clone of the FrC6 virus) induced marked spongiform degeneration in the brain similar to the FrC6 virus, but only mild lesions were found in the spinal cord. In contrast, PVC211 virus, which is also a neuropathogenic F-MuLV variant, caused marked spongiform degeneration in the spinal cord. Virus recovery from the spinal cord of A8 virus-infected rat was the same as that of PVC211-infected rat, indicating that there is no direct correlation between the titer of virus and the intensity of lesions. Furthermore, rats infected with the A8 virus at 3 weeks of age did not undergo spongiform degeneration, although recovery of high titer of virus occurred in the central nervous system (CNS). Studies using chimeric viruses between the A8 virus and nonneuropathogenic F-MuLV clone 57 also indicated that the sequences responsible for virus titers in the CNS and neuropathogenicity are different. The chimeric virus studies proved that the env gene and the LTR and/or 5' leader sequence of A8 are critical for the induction of neuropathogenicity. These sequences in A8 and PVC211 were compared, focusing in on the sites that account for neurovirulence and viral lesional tropism.
Insights
Neuropathogenic Friend Murine Leukemia Virus (F-MuLV) variants A8 and PVC211 cause distinct central nervous system lesions. Specific viral sequences, including the env gene, dictate neurovirulence and lesion tropism, not viral titer alone.
Area of Science:
- Virology
- Neuroscience
- Molecular Biology
Background:
- FrC6 murine leukemia virus (MuLV) is a neuropathogenic variant of Friend MuLV (F-MuLV).
- The A8 and PVC211 viruses are distinct neuropathogenic F-MuLV variants with differing lesion patterns in rats.
Purpose of the Study:
- To investigate the determinants of neuropathogenicity and lesion tropism in F-MuLV variants.
- To differentiate the viral factors responsible for central nervous system (CNS) viral titers versus lesion severity.
Main Methods:
- Comparative analysis of lesion severity and viral titers in rats infected with A8 and PVC211 F-MuLV variants.
- Generation and analysis of chimeric F-MuLV viruses between A8 and a non-neuropathogenic clone (57).
- Sequence comparison of neurovirulence-associated regions in A8 and PVC211.
Main Results:
- A8 virus induced brain spongiform degeneration, while PVC211 primarily affected the spinal cord.
- Viral titer in the spinal cord did not correlate with lesion intensity.
- Infection of young rats with A8 did not cause spongiform degeneration despite high viral CNS titers.
- Chimeric virus studies identified the A8 env gene and LTR/5' leader sequences as critical for neuropathogenicity.
Conclusions:
- Neuropathogenicity of F-MuLV is determined by specific viral genetic elements, not solely by viral replication levels in the CNS.
- The env gene and LTR/5' leader sequences are key determinants of F-MuLV neurovirulence and the resulting lesion tropism.