Lovastatin Inhibits HIV-1-Induced MHC-I Downregulation by Targeting Nef-AP-1 Complex Formation: A New Strategy to Boost Immune Eradication of HIV-1 Infected Cells
Lovastatin Inhibits HIV-1-Induced MHC-I Downregulation by Targeting Nef-AP-1 Complex Formation: A New Strategy to Boost Immune Eradication of HIV-1 Infected Cells
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洛伐他汀通过靶向 Nef-AP-1 复合物形成抑制 HIV-1 诱导的 MHC-I 下调：促进免疫根除 HIV-1 感染细胞的新策略
DOI：
10.3389/fimmu.2019.02151
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发表时间：
2019-09-10
影响因子：
7.3
通讯作者：
Li, Linghua
中科院分区：
文献类型：
--
作者：
Liu, Bingfeng;Zhang, Xu;Li, Linghua
目前的联合抗逆转录病毒疗法（cART）主要针对15种HIV蛋白中的3种，留下许多潜在的病毒脆弱性未被利用。为了清除HIV-1潜伏库，已经开发了包括“休克和杀死”在内的各种策略。一个关键问题是如何恢复受损的免疫监视。HIV-1蛋白Nef长期以来被认为介导细胞表面MHC-I的下调，并协助HIV-1逃避免疫系统。通过对美国食品药品监督管理局（FDA）批准的药物的高通量筛选，我们鉴定了他汀类药物洛伐他汀，其显著拮抗Nef以下调MHC-I、CD 4和SERINC 5，并抑制病毒体的内在感染性。此外，洛伐他汀增强了自体CTL，以根除感染的细胞，并有效抑制随后从接受抑制性cART的HIV-1感染个体中分离的CD 4（+）T淋巴细胞中的病毒反弹。此外，我们发现洛伐他汀通过直接与Nef结合并破坏Nef-AP-1复合物来抑制Nef诱导的MHC-I下调。这些结果表明，洛伐他汀是一种有前途的药物，用于抵消Nef介导的MHC-I，CD 4和SERINC 5的下调。洛伐他汀可能用于临床，以增强抗HIV-1免疫监视。
Current combined antiretroviral therapy (cART) mainly targets 3 of the 15 HIV proteins leaving many potential viral vulnerabilities unexploited. To purge the HIV-1 latent reservoir, various strategies including "shock and kill" have been developed. A key question is how to restore impaired immune surveillance. HIV-1 protein Nef has long been known to mediate the downregulation of cell-surface MHC-I and assist HIV-1 to evade the immune system. Through high throughput screening of Food and Drug Administration (FDA) approved drugs, we identified lovastatin, a statin drug, to significantly antagonize Nef to downregulate MHC-I, CD4, and SERINC5, and inhibit the intrinsic infectivity of virions. In addition, lovastatin boosted autologous CTLs to eradicate the infected cells and effectively inhibit the subsequent viral rebound in CD4(+) T-lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Furthermore, we found that lovastatin inhibits Nef-induced MHC-I downregulation by directly binding with Nef and disrupting the Nef-AP-1 complex. These results demonstrate that lovastatin is a promising agent for counteracting Nef-mediated downregulation of MHC-I, CD4, and SERINC5. Lovastatin could potentially be used in the clinic to enhance anti-HIV-1 immune surveillance.