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Effects of subtle changes in the SU protein of ecotropic murine leukemia virus on its brain capillary endothelial
M Masuda1, C A Hanson, W G Alvord
1Laboratory of Molecular Oncology, National Cancer Institute, Frederick, Maryland 21702, USA.
Abstract:
PVC-211 murine leukemia virus (MuLV) is a neuropathogenic variant of Friend MuLV (F-MuLV) that causes a rapidly progressive neurodegenerative disease in susceptible rodents. PVC-211 MuLV, but not the parental F-MuLV, can infect rat brain capillary endothelial cells (BCEC) efficiently, and the major determinant for BCEC tropism of PVC-211 MuLV is localized within the XbaI-BamHI fragment of the viral genome containing the 5' half of the env gene. To further dissect the XbaI-BamHI region for its effects on BCEC tropism, we constructed recombinant viruses between PVC-211 MuLV and F-MuLV and tested their infectivity on a cell line established from rat BCEC. Our results indicated that Glu116-to-Gly and Glu129-to-Lys substitutions in the background of the F-MuLV envelope SU protein were sufficient for conferring BCEC tropism on the virus. Interference studies of these viruses on Rat-1 fibroblastic cells showed that the structure of the SU protein encoded by the XbaI-BamHI region also has significant effects on their affinity for the rat ecotropic MuLV receptor. These results support the possibility that structural elements I and II of the SU protein are important determinants for virus-receptor interaction.
Insights
Neuropathogenic PVC-211 murine leukemia virus (MuLV) efficiently infects rat brain capillary endothelial cells. Specific envelope SU protein substitutions in Friend MuLV are key to this tropism and virus-receptor interactions.
Area of Science:
- Virology
- Neuroscience
- Molecular Biology
Background:
- PVC-211 murine leukemia virus (MuLV) is a neuropathogenic strain causing neurodegeneration.
- PVC-211 MuLV exhibits efficient tropism for rat brain capillary endothelial cells (BCEC), unlike its parent F-MuLV.
- The viral env gene's 5' half, specifically the XbaI-BamHI fragment, contains the primary determinant for BCEC tropism.
Purpose of the Study:
- To pinpoint the specific viral determinants responsible for PVC-211 MuLV's BCEC tropism.
- To investigate the role of the env gene's XbaI-BamHI region in viral entry into BCEC.
- To understand how viral envelope protein structure influences receptor binding affinity.
Main Methods:
- Construction of recombinant viruses between PVC-211 MuLV and F-MuLV.
- Infectivity assays of recombinant viruses on rat BCEC cell lines.
- Interference studies on Rat-1 fibroblastic cells to assess virus-receptor interactions.
Main Results:
- Two specific amino acid substitutions (Glu116Gly and Glu129Lys) in the F-MuLV SU protein conferred BCEC tropism.
- The XbaI-BamHI region, encoding parts of the SU protein, significantly impacts affinity for the rat ecotropic MuLV receptor.
- Structural elements I and II of the SU protein are implicated as crucial for virus-receptor binding.
Conclusions:
- Specific mutations in the MuLV envelope SU protein dictate tropism for rat brain capillary endothelial cells.
- The findings highlight the importance of viral envelope structure in host cell entry and receptor interactions.
- This research provides insights into the molecular mechanisms underlying MuLV neuropathogenesis.