SIV-specific antibodies protect against inflammasome-driven encephalitis in untreated macaques

• Published in: Cell reports (Cambridge) Vol. 43; no. 10; p. 114833
• Main Authors: Castell, Natalie J., Abreu, Celina M., Shirk, Erin N., Queen, Suzanne E., Mankowski, Joseph L., Clements, Janice E., Veenhuis, Rebecca T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.10.2024; Elsevier
• Subjects: Animals; Antibodies, Viral - immunology; ASC; Brain - immunology; Brain - metabolism; Brain - pathology; CP: Immunology; Encephalitis, Viral - immunology; Encephalitis, Viral - virology; IgG; IL-18; IL-1β; Immunoglobulin G - blood; Immunoglobulin G - cerebrospinal fluid; Immunoglobulin G - immunology; inflammasome; Inflammasomes - immunology; Inflammasomes - metabolism; Macaca; Macaca nemestrina; seroconversion; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - virology; simian immunodeficiency virus; Simian Immunodeficiency Virus - immunology; viral encephalitis; simian immunodeficiency virus; CP: Immunology; ASC; viral encephalitis; seroconversion; inflammasome; IL-18; IgG; IL-1β
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114833

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. [Display omitted] •SIVE is associated with compartmentalized viral replication and cytokine production•Myeloid-dominant lesions show inflammasome activation in infected and bystander cells•SIV-specific IgG responses in the plasma and CSF predict protection from SIVE Outcomes in the SIV-infected macaque model of HIV, including SIV encephalitis (SIVE), are highly variable between animals. Castell et al. find that SIV-specific antibody responses predict protection from SIVE. Plasma and cerebrospinal fluid SIV-specific IgG correlates with reduced brain viral RNA and inflammasome activation and lower compartmentalized CNS cytokine release.