CSF1R inhibition depletes brain macrophages and reduces brain virus burden in SIV-infected macaques

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 r...

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Published in:	Brain (London, England : 1878) Vol. 147; no. 9; pp. 3059 - 3069
Main Authors:	Bohannon, Diana G, Zablocki-Thomas, Laurent D, Leung, Evan S, Dupont, Jinbum K, Hattler, Julian B, Kowalewska, Jolanta, Zhao, Miaoyun, Luo, Jiangtao, Salemi, Marco, Amedee, Angela M, Li, Qingsheng, Kuroda, Marcelo J, Kim, Woong-Ki
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 03-09-2024
Subjects:	Animals Anisoles Antigens, CD - metabolism Antigens, Differentiation, Myelomonocytic - metabolism Brain - drug effects Brain - metabolism Brain - virology Macaca mulatta Macrophages - drug effects Macrophages - metabolism Male Microglia - drug effects Microglia - metabolism Microglia - virology Original Pyrimidines - pharmacology Pyrimidines - therapeutic use Receptors, Cell Surface - metabolism Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism Simian Acquired Immunodeficiency Syndrome - drug therapy Simian Acquired Immunodeficiency Syndrome - immunology Simian Immunodeficiency Virus - drug effects Viral Load - drug effects CSF1R SIV BLZ945 perivascular macrophage HIV
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Diana G Bohannon and Laurent D Zablocki-Thomas contributed equally to this work.
ISSN:	0006-8950 1460-2156 1460-2156
DOI:	10.1093/brain/awae153