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Analysis of Simian Immunodeficiency Virus-specific CD8+ T-cells in Rhesus Macaques by Peptide-MHC-I Tetramer Staining
Published on: December 23, 2016
SIV-specific antibodies protect against inflammasome-driven encephalitis in untreated macaques
Natalie J Castell1, Celina M Abreu1, Erin N Shirk1
1Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract:
Viral encephalitis is a growing public health threat with limited diagnostic and treatment options. Simian immunodeficiency virus (SIV)-infected macaques are an established model for human immunodeficiency virus (HIV), and approximately 60% of untreated pigtail macaques rapidly progress to characteristic SIV encephalitis (SIVE). The immune responses of SIV-infected macaques are investigated in plasma, cerebrospinal fluid (CSF), and brain tissue to determine correlates with SIVE pathology. Macaques with SIVE show myeloid-dominant brain lesions with inflammasome activation in infected and bystander cells, as assessed by interleukin (IL)-1β, IL-18, and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and elevations in monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and tumor necrosis factor alpha (TNF-α). SIV-specific immunoglobulin (Ig)G in plasma and CSF is predictive of SIVE as early as 21 days post-inoculation; animals with SIVE continue to show negligible seroconversion 3 months after infection. This dichotomy in immune responses, wherein some macaques fail to initiate robust IgG responses and subsequently develop SIVE, provides insight into the pathogenesis and heterogeneous outcomes in viral encephalitis.
Insights
Simian immunodeficiency virus encephalitis (SIVE) in macaques involves myeloid brain lesions and inflammasome activation. Poor immunoglobulin G (IgG) response predicts SIVE, offering insights into viral encephalitis pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Viral encephalitis poses a significant public health challenge with limited therapeutic and diagnostic tools.
- Simian immunodeficiency virus (SIV)-infected macaques serve as a critical model for studying human immunodeficiency virus (HIV) and its neurological complications.
- A substantial proportion of untreated pigtail macaques develop SIV encephalitis (SIVE), mirroring aspects of HIV neuropathogenesis.
Purpose of the Study:
- To investigate immune responses in plasma, cerebrospinal fluid (CSF), and brain tissue of SIV-infected macaques.
- To identify immune correlates associated with the development of SIV encephalitis (SIVE) pathology.
- To understand the mechanisms underlying the heterogeneous outcomes observed in viral encephalitis.
Main Methods:
- Analysis of immune markers in plasma, CSF, and brain tissue from SIV-infected macaques.
- Assessment of inflammasome activation using interleukin (IL)-1β, IL-18, and ASC.
- Quantification of chemokines (MCP-1, MIP-1α) and cytokines (TNF-α).
- Evaluation of SIV-specific immunoglobulin G (IgG) seroconversion over time.
Main Results:
- Macaques with SIVE exhibited myeloid-dominant brain lesions characterized by inflammasome activation (IL-1β, IL-18, ASC).
- Elevated levels of MCP-1, MIP-1α, and TNF-α were observed in macaques with SIVE.
- SIV-specific IgG in plasma and CSF predicted SIVE development as early as 21 days post-inoculation.
- Animals developing SIVE showed minimal seroconversion even after 3 months.
Conclusions:
- A dichotomy exists in immune responses, with a failure to mount robust IgG responses correlating with SIVE development.
- These findings provide crucial insights into the pathogenesis of SIV encephalitis and the varied clinical outcomes in viral encephalitis.
- Understanding these immune dysregulations can inform the development of novel diagnostic and therapeutic strategies for viral encephalitis.
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