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Two separate envelope regions influence induction of brain disease by a polytropic murine retrovirus (FMCF98)
K J Hasenkrug1, S J Robertson, J Porti
1Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA. Kim Hasenkrug@rml.niaid.pc.niaid.nih.gov
Abstract:
The major determinants involved in neurological disease induction by polytropic murine leukemia virus FMCF98 are encoded by the envelope gene. To map these determinants further, we produced four chimeras which contained neurovirulent FMCF98 envelope sequences combined with envelope sequences from the closely related nonneurovirulent polytropic virus FMCF54. Surprisingly, two chimeric viruses containing completely separate envelope regions from FMCF98 could both induce neurological disease. Clinical signs caused by both neurovirulent chimeras appeared to be indistinguishable from those caused by FMCF98, although the incubation periods were longer. One neurovirulence determinant mapped to the N-terminal portion of gp7O, which contains the VRA and VRB receptor-binding regions, while the other determinant mapped downstream of both of the variable regions. Western blot (immunoblot) analyses and immunohistochemical staining of tissue sections indicated that the variations in neurovirulence of these viruses could not be explained by differences in either the quantitative level or the location of virus expression in the brain.
Insights
Researchers identified key viral envelope gene regions responsible for causing neurological disease in mice. These findings advance understanding of polytropic murine leukemia virus (MLV) pathogenesis and neurovirulence.
Area of Science:
- Virology
- Neuroscience
- Molecular Biology
Background:
- Polytropic murine leukemia virus (MLV) can cause neurological diseases.
- The envelope gene of MLV is crucial for its neurovirulence.
Purpose of the Study:
- To further map the specific determinants within the MLV envelope gene responsible for inducing neurological disease.
- To investigate the roles of different envelope gene regions in MLV neurovirulence.
Main Methods:
- Construction and analysis of four chimeric polytropic MLV viruses.
- Combining envelope gene sequences from neurovirulent (FMCF98) and non-neurovirulent (FMCF54) strains.
- Clinical observation of induced neurological signs in mice.
- Western blot and immunohistochemical analyses of viral expression in brain tissues.
Main Results:
- Two chimeric viruses, each containing distinct FMCF98 envelope regions, induced neurological disease.
- Clinical signs were similar to the parent FMCF98 strain, but with longer incubation periods.
- One neurovirulence determinant was located in the N-terminal gp70, including VRA and VRB regions.
- A second determinant was mapped downstream of these variable regions.
- Viral expression levels and localization in the brain did not explain the observed neurovirulence variations.
Conclusions:
- The MLV envelope gene contains multiple, distinct determinants that contribute to neurovirulence.
- These determinants can function independently to induce neurological disease.
- Neurovirulence is not solely dependent on the quantitative or spatial expression of the virus in the brain.