Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro
Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro
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DOI：
10.1186/s12974-019-1565-6
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发表时间：
2019-09-27
影响因子：
9.3
通讯作者：
Tyor, William R.
中科院分区：
文献类型：
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作者：
Gavegnano, Christina;Haile, Woldeab B.;Tyor, William R.
由于高达一半的HIV阳性个体发生HIV相关神经认知障碍（HANDs），即使采用联合抗逆转录病毒治疗（cART），也需要持续治疗。慢性CNS炎症导致HAND和HIV脑炎（HIVE）。Baricitinib是一种JAK 1/2抑制剂，在美国、欧盟和日本获批用于类风湿性关节炎，对IL-6、D-二聚体、CRP、TNF-α、IFN-α/β和其他促炎细胞因子具有强效抑制作用。方法采用改良的小鼠HAND模型评价baricitinib通过血脑屏障（BBB）和调节单核/巨噬细胞驱动的HAND的能力。通过评估低剂量和高剂量baricitinib治疗与未治疗的HAND小鼠的认知表现来测量HAND的严重程度。在流式细胞术分析后，在这些小鼠组中评价脑神经炎症的严重程度。我们还评估了baricitinib在体外阻断髓样和淋巴样细胞中可能导致HIV在中枢神经系统（CNS）原代人巨噬细胞（M phi）和淋巴细胞中持续存在的事件的能力，包括HIV复制、HIV诱导的激活、储库扩张和储库维持。结果在体内，10和50 mg/kg qd baricitinib剂量均能穿过血脑屏障，逆转HIV感染引起的行为异常。此外，baricitinib显着减少了HIV诱导的神经炎症标志着神经胶质细胞活化：活化的小胶质细胞（MHCII+/CD 45（+））和星形胶质细胞增生（GFAP）。Baricitinib还显著降低了小鼠脑中p24+人巨噬细胞的百分比（p < 0.05，相对于HAND小鼠; t检验）。在体外，baricitinib显着减少标记物的持久性，水库大小，并重新接种在M phi。结论阻断JAK/STAT通路可逆转小鼠认知功能障碍，并减少HAND中的炎症标志物。我们的小组最近报道了鲁索利替尼在HIV感染个体中的安全性和耐受性（Marconi等人，ruxolitinib添加到抑制性ART中的安全性，耐受性和免疫活性，2019），强调了JAK抑制剂用于其他人体试验的潜在安全性和实用性。本文报告的数据加上我们最近使用JAK抑制剂的人体试验，为考虑在接受cART治疗的HAND个体中进行baricitinib试验以逆转认知缺陷和驱动病毒持续性的关键事件提供了令人信服的临床前数据和动力。
Background 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-alpha, IFN-alpha/beta, and other pro-inflammatory cytokines. Methods 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 (M phi) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. Results 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 M phi. Conclusion 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.