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.

中文翻译：

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CSF1R 抑制可消耗 SIV 感染猕猴的脑巨噬细胞并减轻脑病毒负荷


血管周围巨噬细胞 （PVM） 和小胶质细胞（在较小程度上）是大脑中 HIV 和猿猴免疫缺陷病毒 （SIV） 的靶标和宿主。以前，我们证明 PVM 中的集落刺激因子 1 受体 （CSF1R） 在慢性 SIV 感染的恒河猴脑炎中上调和激活，与 PVM 的 SIV 感染相关。在此，我们使用 BLZ945（一种脑渗透性 CSF1R 激酶抑制剂）研究了 CSF1R 在急性 SIV 感染期间大脑中的作用。除了 3 个未感染的历史对照外，9 只印度恒河猴急性感染了 SIVmac251，并分为三组（每组 n = 3）：一组未治疗的对照和两组用低剂量（10 mg/kg/天）或高剂量（30 mg/kg/天）治疗 20-30 天 BLZ945。与低剂量治疗组和对照组相比，高剂量 BLZ945 治疗后，在所有检查的四个大脑区域中表达 CD163 和 CD206 的细胞显着减少。在 11 个测试区域中的 9 个区域，组织病毒 DNA （vDNA） 载量在两次给药中的至少一次后降低了 95%-99%，在某些情况下甚至降低到检测不到的水平。CD163 + 和 CD206 + 细胞数量的减少与所有四个相应大脑区域中 vDNA 水平的降低显著相关。相比之下，BLZ945 治疗对小胶质细胞的数量没有显着影响。我们的结果表明，低至 10 mg/kg/天的 BLZ945 剂量足以减少大脑中的组织 vDNA 负荷，而没有明显的不利影响。这项研究提供了证据表明，感染的 PVM 对 CSF1R 抑制高度敏感，为实现病毒清除开辟了新的可能性。