SERPIN-Derived Small Peptide (SP16) as a Potential Therapeutic Agent against HIV-Induced Inflammatory Molecules and Viral Replication in Cells of the Central Nervous System.
SERPIN-Derived Small Peptide (SP16) as a Potential Therapeutic Agent against HIV-Induced Inflammatory Molecules and Viral Replication in Cells of the Central Nervous System.
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SERPIN衍生的小肽（SP16）是中枢神经系统细胞中针对HIV诱导的炎症分子和病毒复制的潜在治疗剂。
作者：
尽管联合抗逆转录病毒疗法（cART）成功提高了人类免疫缺陷病毒（HIV）患者的存活率，但患者脑中持续存在低水平的病毒血症，导致神经胶质细胞（小胶质细胞和星形胶质细胞）诱导的神经炎症，从而导致HIV的再活化和神经元损伤。在这里，我们测试了低密度脂蛋白受体相关蛋白1（LRP-1）激动性小肽药物（SP16）在减弱HIV复制和脑储库中炎症分子分泌方面的治疗效果。SP16由Serpin Pharma开发，来源于丝氨酸蛋白酶抑制剂α-1-抗胰蛋白酶（A1 AT）的五肽序列。随后对SP16肽序列进行修饰以改善稳定性、生物利用度、功效和与LRP-1的结合; LRP-1是一种清道夫调节受体，其内化配体以诱导抗病毒、抗炎和促存活信号。使用感染HIV的神经胶质细胞，我们发现：（i）SP16减弱了病毒诱导的促炎分子分泌;（ii）SP16减弱了病毒复制。使用人工3D血脑屏障（BBB）系统，我们表明：（i）SP16被转运穿过BBB;和（ii）恢复由HIV损害的BBB的通透性。从机制上讲，我们发现SP16与LRP-1的相互作用和结合导致：（i）核因子-κ β（NF-κB）表达水平下调;（ii）Akt表达水平上调。使用体内小鼠模型，我们表明SP16在鼻内递送后被转运穿过BBB，而感染EcoHIV的动物在暴露于SP16和抗逆转录病毒药物后经历（i）病毒复制和（ii）病毒分泌的炎症分子的减少。总体而言，这些研究证实了SP16对大脑中HIV相关炎症作用的治疗反应。
Despite the success of combined antiretroviral therapy (cART) increasing the survival rate in human immunodeficiency virus (HIV) patients, low levels of viremia persist in the brain of patients leading to glia (microglia and astrocytes)-induced neuroinflammation and consequently, the reactivation of HIV and neuronal injury. Here, we tested the therapeutic efficacy of a Low-Density Lipoprotein Receptor-Related Protein 1 (LRP-1) agonistic small peptide drug (SP16) in attenuating HIV replication and the secretion of inflammatory molecules in brain reservoirs. SP16 was developed by Serpin Pharma and is derived from the pentapeptide sequence of the serine protease inhibitor alpha-1-antitrypsin (A1AT). The SP16 peptide sequence was subsequently modified to improve the stability, bioavailability, efficacy, and binding to LRP-1; a scavenger regulatory receptor that internalizes ligands to induce anti-viral, anti-inflammatory, and pro-survival signals. Using glial cells infected with HIV, we showed that: (i) SP16 attenuated viral-induced secretion of pro-inflammatory molecules; and (ii) SP16 attenuated viral replication. Using an artificial 3D blood-brain barrier (BBB) system, we showed that: (i) SP16 was transported across the BBB; and (ii) restored the permeability of the BBB compromised by HIV. Mechanistically, we showed that SP16 interaction with LRP-1 and binding lead to: (i) down-regulation in the expression levels of nuclear factor-kappa beta (NF-κB); and (ii) up-regulation in the expression levels of Akt. Using an in vivo mouse model, we showed that SP16 was transported across the BBB after intranasal delivery, while animals infected with EcoHIV undergo a reduction in (i) viral replication and (ii) viral secreted inflammatory molecules, after exposure to SP16 and antiretrovirals. Overall, these studies confirm a therapeutic response of SP16 against HIV-associated inflammatory effects in the brain.
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DOI：
10.1097/qad.0b013e3283639804
发表时间：
2013-09-10
期刊：
AIDS (London, England)
影响因子：
--
作者：
El-Hage N;Dever SM;Podhaizer EM;Arnatt CK;Zhang Y;Hauser KF
通讯作者：
Hauser KF
影响因子：
3.2
作者：
Beck SE;Queen SE;Metcalf Pate KA;Mangus LM;Abreu CM;Gama L;Witwer KW;Adams RJ;Zink MC;Clements JE;Mankowski JL
通讯作者：
Mankowski JL
影响因子：
20.3
作者：
Gaultier, Alban;Arandjelovic, Sanja;Gonias, Steven L.
通讯作者：
Gonias, Steven L.
影响因子：
4.8
作者：
Fuentealba, Rodrigo A.;Liu, Qiang;Bu, Guojun
通讯作者：
Bu, Guojun
影响因子：
4.6
作者：
Alhalaweh, Amjad;Andersson, Staffan;Velaga, Sitaram P.
通讯作者：
Velaga, Sitaram P.