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Efficient infection of brain microvascular endothelial cells by an in vivo-selected neuroinvasive SIVmac variant
L I Strelow1, D D Watry, H S Fox
1Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland 97201, USA.
Abstract:
A neuroinvasive/neuropathogenic SIV variant termed SIVmac182 was previously isolated and characterized (Watry et al, 1994). This neuroinvasive strain was derived from the uncloned strain SIVmac251 through serial animal passage of infected microglia, unlike previously reported neurovirulent strains. Importantly, the virus described here was isolated from a strain which already demonstrates limited neuroinvasiveness in vivo, through a route of inoculation which exerts selective pressure for variants in the periphery that can naturally cross the blood-brain barrier and gain access to the brain. Examination of animal tissues indicated that the neuroinvasive strain was capable of replicating in brain microvascular endothelial cells (BMEC). Therefore, we developed an in vitro model of BMEC infection in which to examine mechanisms of virus neuroinvasiveness and neuropathogenicity as well as to address mechanisms of HIV-induced dementia. Results obtained with this in vitro system indicate that growth in BMEC may predict neuroinvasiveness in vivo, and furthermore, that brain passage of virus results in the generation of neuroinvasive strains which demonstrate an increased efficiency of BMEC infection in vitro.
Insights
A novel simian immunodeficiency virus (SIV) strain, SIVmac182, demonstrates neuroinvasiveness by infecting brain microvascular endothelial cells (BMEC). This finding offers insights into HIV dementia mechanisms and viral entry into the central nervous system.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- A neuroinvasive simian immunodeficiency virus (SIV) variant, SIVmac182, was previously isolated.
- This strain originated from SIVmac251 via serial animal passage of infected microglia.
- Previous neurovirulent strains were derived differently, highlighting the unique origin of SIVmac182.
Purpose of the Study:
- To investigate the mechanisms of SIV neuroinvasiveness and neuropathogenicity.
- To develop an in vitro model for studying viral entry into the brain.
- To explore mechanisms underlying HIV-induced dementia.
Main Methods:
- Isolation and characterization of a neuroinvasive SIV variant (SIVmac182).
- Development of an in vitro model using brain microvascular endothelial cells (BMEC).
- Examination of animal tissues to confirm viral replication in BMEC.
Main Results:
- SIVmac182 was found to replicate in brain microvascular endothelial cells (BMEC).
- In vitro BMEC infection correlated with in vivo neuroinvasiveness.
- Viral passage through the brain generated strains with enhanced BMEC infectivity.
Conclusions:
- BMEC infection serves as a potential predictor of in vivo neuroinvasiveness.
- Brain passage selects for SIV variants with increased ability to infect BMEC.
- This research provides a model to study viral entry into the brain and HIV dementia.