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Narrowing down the critical region within env gene for determining neuropathogenicity of murine leukemia virus A8
Yohei Seki1, Naoki Hirano, Misaho Mizukura
1Department of Bioinformatics, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan.
Abstract:
Friend murine leukemia virus clone A8 causes spongiform neurodegeneration in the rat brain, and the env gene of A8 is a primary determinant of neuropathogenicity. In order to narrow down the critical region within the env gene that determines neuropathogenicity, we constructed chimeric viruses having chimeric env between A8 and non-neuropathogenic 57 on the background of A8 virus. After replacement of the BamHI (at nucleotide 5715)-AgeI (at nucleotide 6322) fragment of A8 virus with the corresponding fragment of 57, neuropathogenicity was lost. In contrast, the chimeric viruses that have the BamHI (5715)-AgeI (6322) fragment of A8 induced spongiosis in 100% of infected rats at the same or slightly lower intensity than A8 virus. These results indicate that the BamHI (5715)-AgeI (6322) fragment of A8, which contains the signal sequence and the N-terminal half of RBD, is crucial for the induction of spongiform neurodegeneration. In the BamHI (5715)-AgeI (6322) fragment, seven amino acids differed between A8 and 57, one in the signal sequence and six in RBD, which suggests that these amino acids significantly contribute to the neuropathogenicity of A8.
Insights
Friend murine leukemia virus clone A8 causes spongiform neurodegeneration. The env gene
Area of Science:
- Virology
- Neuroscience
- Molecular Biology
Background:
- Friend murine leukemia virus clone A8 induces spongiform neurodegeneration in rats.
- The env gene of A8 is a key factor in its neuropathogenicity.
Purpose of the Study:
- To identify the specific region within the env gene responsible for A8's neuropathogenicity.
- To construct and analyze chimeric viruses with modified env genes.
Main Methods:
- Construction of chimeric viruses by exchanging env gene fragments between A8 and a non-neuropathogenic strain (57).
- Analysis of neuropathogenicity in rats infected with chimeric viruses.
- Identification of critical DNA fragments using restriction enzymes BamHI and AgeI.
Main Results:
- Replacing the BamHI-AgeI fragment (nucleotides 5715-6322) of A8 env with the corresponding fragment from strain 57 abolished neuropathogenicity.
- Chimeric viruses retaining the A8 BamHI-AgeI fragment induced spongiosis in all infected rats.
- This critical fragment contains the signal sequence and N-terminal half of the receptor-binding domain (RBD).
Conclusions:
- The BamHI-AgeI fragment of the A8 env gene is essential for inducing spongiform neurodegeneration.
- Specific amino acid differences within this fragment, particularly in the signal sequence and RBD, likely drive neuropathogenicity.
