Yadav Anjana, Betts Michael R, Collman Ronald G
Department of Medicine, University of Pennsylvania Perelman School of Medicine, 36th and Hamilton Walk, Philadelphia, PA, 19104, USA.
Department of Microbiology, University of Pennsylvania Perelman School of Medicine, 36th and Hamilton Walk, Philadelphia, PA, 19104, USA.
J Neurovirol. 2016 Oct;22(5):584-596. doi: 10.1007/s13365-016-0433-8. Epub 2016 Mar 28.
HIV-1-associated neurocognitive disorder (HAND) remains a persistent problem despite antiretroviral therapy (ART), largely a result of continued inflammation in the periphery and the brain and neurotoxin release from activated myeloid cells in the CNS. CD14+CD16+ inflammatory monocytes, expanded in HIV infection, play a central role in the pathogenesis of HAND and have parallels with monocyte-dependent inflammatory mechanisms in atherosclerosis. Statins, through their HMG-CoA reductase inhibitor activity, have pleiotropic immunomodulatory properties that contribute to their benefit in atherosclerosis beyond lipid lowering. Here, we investigated whether statins would modulate the monocyte phenotype and function associated with HIV-1 neuropathogenesis. Treatment ex vivo with simvastatin and atorvastatin reduced the proportion of CD16+ monocytes in peripheral blood mononuclear cells, as well as in purified monocytes, especially CD14++CD16+ "intermediate" monocytes most closely associated with neurocognitive disease. Statin treatment also markedly reduced expression of CD163, which is also linked to HAND pathogenesis. Finally, simvastatin inhibited production of monocyte chemoattractant protein-1 (MCP-1) and other inflammatory cytokines following LPS stimulation and reduced monocyte chemotaxis in response to MCP-1, a major driver of myeloid cell accumulation in the CNS in HAND. Together, these findings suggest that statin drugs may be useful to prevent or reduce HAND in HIV-1-infected subjects on ART with persistent monocyte activation and inflammation.
尽管有抗逆转录病毒疗法（ART），但HIV-1相关神经认知障碍（HAND）仍然是一个持续存在的问题，这主要是由于外周和大脑持续存在炎症以及中枢神经系统中活化髓样细胞释放神经毒素所致。在HIV感染中扩增的CD14+CD16+炎性单核细胞在HAND的发病机制中起核心作用，并且与动脉粥样硬化中单核细胞依赖性炎症机制相似。他汀类药物通过其HMG-CoA还原酶抑制剂活性具有多效性免疫调节特性，这有助于它们在动脉粥样硬化中除降脂之外的益处。在此，我们研究了他汀类药物是否会调节与HIV-1神经发病机制相关的单核细胞表型和功能。用辛伐他汀和阿托伐他汀进行体外处理可降低外周血单核细胞以及纯化单核细胞中CD16+单核细胞的比例，尤其是与神经认知疾病最密切相关的CD14++CD16+“中间”单核细胞。他汀类药物治疗还显著降低了与HAND发病机制也相关的CD163的表达。最后，辛伐他汀抑制了脂多糖刺激后单核细胞趋化蛋白-1（MCP-1）和其他炎性细胞因子的产生，并降低了对MCP-1的单核细胞趋化性，MCP-1是HAND中中枢神经系统髓样细胞积聚的主要驱动因素。总之，这些发现表明他汀类药物可能有助于预防或减少接受ART但存在持续单核细胞活化和炎症的HIV-1感染受试者的HAND。
