Abstract
HIV-associated neuroinflammation is primarily driven by CNS macrophages including microglia. Regulation of these immune responses, however, remains to be characterized in detail. Using the SIV/macaque model of HIV, we evaluated CNS expression of triggering receptor expressed on myeloid cells 2 (TREM2) which is constitutively expressed by microglia and contributes to cell survival, proliferation, and differentiation. Loss-of-function mutations in TREM2 are recognized risk factors for neurodegenerative diseases including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Nasu-Hakola disease (NHD); recent reports have also indicated a role for TREM2 in HIV-associated neuroinflammation. Using in situ hybridization (ISH) and qRT-PCR, TREM2 mRNA levels were found to be significantly elevated in frontal cortex of macaques with SIV encephalitis compared with uninfected controls (P = 0.02). TREM2 protein levels were also elevated as measured by ELISA of frontal cortex tissue homogenates in these animals. Previously, we characterized the expression of CSF1R (colony-stimulating factor 1 receptor) in this model; the TREM2 and CSF1R promoters both contain a PU.1 binding site. While TREM2 and CSF1R mRNA levels in the frontal cortex were highly correlated (Spearman R = 0.79, P < 0.001), protein levels were not well correlated. In SIV-infected macaques released from ART to study viral rebound, neither TREM2 nor CSF1R mRNA increased with rebound viremia. However, CSF1R protein levels remained significantly elevated unlike TREM2 (P = 0.02). This differential expression suggests that TREM2 and CSF1R play unique, distinct roles in the pathogenesis of HIV CNS disease.
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Acknowledgments
We thank Lisa Mangus, Sarah Beck, Andrew Johanson, and the members of the JHU Retrovirus Laboratory for their contributions. We also thank Drs Feilim MacGabhann, H. Benjamin Larman, and Norman Haughey for their valuable insight and input.
Funding
Funding was provided by NIH R01NS089482, NIH R01NS077869, NIH R01 NS097221, and U42 OD013117. Gilead Sciences, Inc. Foster City, CA, and ViiV Healthcare US, Raleigh, NC, generously donated anti-retroviral compounds.
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Supplemental Figure 1
TREM2 ISH colocalizes with IBA1+ CNS macrophages. (A) The double IHC-ISH staining showed that TREM2 ISH (red) colocalizes with IBA1+ cells (brown) in an SIV infected pigtailed macaque with encephalitis. (B) Fluorescence was used to highlight TREM2 ISH staining (red channel). (PNG 3105 kb)
Supplemental Table 1
Study Animals. Description of animals from which samples were taken for the studies described in this paper. (DOCX 16 kb)
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Knight, A.C., Brill, S.A., Solis, C.V. et al. Differential regulation of TREM2 and CSF1R in CNS macrophages in an SIV/macaque model of HIV CNS disease. J. Neurovirol. 26, 511–519 (2020). https://doi.org/10.1007/s13365-020-00844-1
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DOI: https://doi.org/10.1007/s13365-020-00844-1