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Tulane University School of Medicine

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Brain, Jul 25 2024, awae153 | https://doi.org/10.1093/brain/awae153 CSF1R inhibition depletes brain macrophages and reduces brain virus burden in SIV-infected macaques

Diana G. Bohannon,^1,† Laurent D. Zablocki-Thomas,^2,† Evan S. Leung,¹ Jinbum K. Dupont,¹ Julian B. Hattler,¹ Jolanta Kowalewska,³ Miaoyun Zhao,⁴ Jiangtao Luo,⁵ Marco Salemi,⁶ Angela M. Amedee,⁷ Qingsheng Li,⁴ Marcelo J. Kuroda² and Woong-Ki Kim^1,8,9

¹Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA

²Department of Anatomy, Physiology & Cell Biology, University California, Davis School of Veterinary Medicine, Davis, CA 95616, USA

³Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA 23507, USA

⁴Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA

⁵Department of Health Systems and Population Health Sciences, the Tilman J. Fertitta Family College of Medicine, University of Houston, Houston, TX 77204, USA

⁶Department of Epidemiology, University of Florida College of Medicine, Gainesville, FL 32610, USA

⁷Department of Microbiology, Immunology & Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

⁸Division of Microbiology, Tulane National Primate Research Center, Covington, LA, 70433, USA

⁹Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA

^†These authors contributed equally to this work.

Correspondence to: Woong-Ki Kim

Abstract

Perivascular macrophages (PVMs) and, to a lesser degree, microglia are targets and reservoirs of HIV and simian immunodeficiency virus (SIV) in the brain. Previously, we demonstrated that colony-stimulating factor 1 receptor (CSF1R) in PVMs was upregulated and activated in chronically SIV-infected rhesus macaques with encephalitis, correlating with SIV infection of PVMs. Herein, we investigated the role of CSF1R in the brain during acute SIV infection using BLZ945, a brain-penetrant CSF1R kinase inhibitor. Apart from three uninfected historic controls, nine Indian rhesus macaques were infected acutely with SIVmac251 and divided into three groups (n = 3 each): an untreated control and two groups treated for 20-30 days with low- (10 mg/kg/day) or high- (30 mg/kg/day) dose BLZ945. With the high-dose BLZ945 treatment, there was a significant reduction in cells expressing CD163 and CD206 across all four brain areas examined, compared with the low-dose treatment and control groups. In 9 of 11 tested regions, tissue viral DNA (vDNA) loads were reduced by 95%-99% following at least one of the two doses, and even to undetectable levels in some instances. Decreased numbers of CD163+ and CD206+ cells correlated significantly with lower levels of vDNA in all four corresponding brain areas. In contrast, BLZ945 treatment did not significantly affect the number of microglia. Our results indicate that doses as low as 10 mg/kg/day of BLZ945 are sufficient to reduce the tissue vDNA loads in the brain with no apparent adverse effect. This study provides evidence that infected PVMs are highly sensitive to CSF1R inhibition, opening new possibilities to achieve viral clearance.

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형식Research article
게재일2024년 07월 (BRIC 등록일 2024-08-02)
연구진국외 연구진
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