Chimeric Theiler's virus with altered tropism for the central nervous system

Area of Science:

• Neurovirology
• Picornavirus research
• Central nervous system (CNS) infections

Background:

• Theiler's virus, a neurotropic murine picornavirus, causes encephalitis or persistent demyelinating disease.
• Demyelinating strains migrate sequentially through the CNS, leading to chronic demyelination.
• Neurovirulent strains cause fatal encephalitis via lytic neuronal infection.

Purpose of the Study:

• Investigate the role of the viral capsid in Theiler's virus tropism and disease progression.
• Characterize the behavior of a novel chimeric virus (R5) with altered capsid proteins.

Main Methods:

• Construction of a recombinant Theiler's virus (R5) using genetic material from neurovirulent (GDVII) and persistent (DA) strains.
• Intracranial inoculation of R5 into immunocompetent (SJL/J, BALB/c) and immunodeficient (BALB/c nu/nu) mice.
• Analysis of viral replication, persistence, and distribution within the CNS.

Main Results:

• Chimeric virus R5, with a modified capsid (VP1, VP3), did not persist in immunocompetent mice.
• R5 replicated efficiently and persisted in the CNS of immunodeficient BALB/c nu/nu mice.
• Unlike the DA strain, R5 did not cause mortality in BALB/c nu/nu mice, remaining in the brain's grey matter and avoiding the spinal cord's white matter.

Conclusions:

• The viral capsid contains determinants crucial for Theiler's virus persistence and CNS migration patterns.
• Specific capsid alterations in R5 restrict its neurotropism, preventing white matter colonization and demyelination.
• These findings highlight the capsid's significant role in dictating the characteristic spread of Theiler's virus within the CNS.