Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, 30322, USA.
Emory Center for AIDS Research (CFAR), Emory University, Atlanta, GA, 30322, USA.
J Neuroinflammation. 2019 Sep 27;16(1):182. doi: 10.1186/s12974-019-1565-6.
Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/β, and other pro-inflammatory cytokines.
Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance.
In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII/CD45) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ.
These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.
由于 HIV 相关神经认知障碍（HAND）在接受联合抗逆转录病毒治疗（cART）的 HIV 阳性个体中发生率高达一半，因此需要辅助治疗。慢性中枢神经系统炎症是 HAND 和 HIV 脑炎（HIVE）的病因之一。巴瑞替尼是一种在美国、欧盟和日本获批用于治疗类风湿关节炎的 JAK1/2 抑制剂，具有强大的抑制白细胞介素 6、D-二聚体、C 反应蛋白、肿瘤坏死因子-α、干扰素-α/β 和其他促炎细胞因子的作用。
我们使用改良的 HIV 相关 HAND 模型来评估巴瑞替尼穿透血脑屏障（BBB）和调节单核细胞/巨噬细胞驱动的 HAND 的能力。通过评估低剂量和高剂量巴瑞替尼治疗与未治疗 HAND 小鼠的认知表现来衡量 HAND 的严重程度。在这些小鼠组中，通过流式细胞术分析评估脑神经炎症的严重程度。我们还评估了巴瑞替尼在体外阻断髓样细胞和淋巴样细胞中可能导致 HIV 持续存在于中枢神经系统（CNS）的事件的能力，这些事件包括 HIV 复制、HIV 诱导的激活、储库扩张和储库维持。
体内，10 和 50mg/kg qd 两种剂量的巴瑞替尼均可穿透 BBB，并逆转 HIV 感染引起的行为异常。此外，巴瑞替尼显著降低了由 HIV 诱导的神经炎症标志物，包括小胶质细胞（MHCII/CD45）和星形胶质细胞（GFAP）的激活。巴瑞替尼还显著降低了小鼠大脑中 p24+人巨噬细胞的比例（与 HAND 小鼠相比，p<0.05；t 检验）。体外，巴瑞替尼显著降低了巨噬细胞中持续性、储库大小和再播种的标志物。
这些结果表明，阻断 JAK/STAT 通路可逆转 HAND 小鼠的认知缺陷并减少炎症标志物。我们的研究小组最近报告了 ruxolitinib 在 HIV 感染者中的安全性和耐受性（Marconi 等人，Safety， tolerability and immunologic activity of ruxolitinib added to suppressive ART，2019），突出了 JAK 抑制剂在进一步人体试验中的潜在安全性和实用性。本文报告的数据加上我们最近的 JAK 抑制剂人体试验提供了令人信服的临床前数据，并为考虑在接受 cART 治疗的 HAND 个体中使用巴瑞替尼治疗以逆转认知缺陷和驱动病毒持续存在的关键事件提供了动力。
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