Astrocyte Infection Is Required for Retrovirus-Induced Spongiform Neurodegeneration Despite Suppressed Viral Protein...

Area of Science:

• Virology
• Neuroscience
• Cell Biology

Background:

• Retrovirus (RV) neurodegeneration depends on envelope protein (Env) activities: viral entry and indirect neuronal alteration.
• Identifying specific CNS target cells and understanding virus suppression are crucial for neuropathogenesis research.

Purpose of the Study:

• To investigate how neurotropism differences between ecotropic and amphotropic murine leukemia viruses (MLVs) influence neurovirulence.
• To determine the causal role of specific CNS cell types in retroviral neuropathogenesis.

Main Methods:

• Ex vivo neurotropism analysis using primary glial cell cultures and neural progenitor cell (NPC)-neural stem cell (NSC) chimeras.
• In vivo CNS tropism assessment via NSC transplant-based Cre-vector pseudotyping in reporter mice.
• Comparison of ecotropic (FrCasE) and amphotropic (FrAmE) virus targeting in the CNS.

Main Results:

• Primary astrocytes and NPCs restrict amphotropic virus entry but not ecotropic virus entry.
• Ecotropic virus (FrCasE) targets glia, endothelia, but not neurons; widespread virus suppression (62% lack Env expression) was observed.
• Ecotropic packaging NSCs identified microglia, OPCs, endothelia, and notably, protoplasmic astrocytes as targets; FrCasE showed fourfold higher astrocyte targeting than FrAmE.

Conclusions:

• Astrocyte infection is a major requirement for retroviral-induced neurodegeneration, particularly when associated with ecotropic Env pseudotyping.
• Minimal, even subdetectable, viral Env protein expression in astrocytes is sufficient to alter neuronal physiology.
• Subdetectable astrocyte expression of exogenous or endogenous RVs may contribute significantly to human and animal neurodegenerative diseases.