Chandel Nirupama, Ayasolla Kamesh, Lan Xiqian, Rai Partab, Mikulak Joanna, Husain Mohammad, Malhotra Ashwani, McGowan Joseph, Singhal Pravin C
Center of Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore LIJ Hofstra Medical School, Manhasset, New York, USA; and.
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
J Leukoc Biol. 2014 Oct;96(4):601-9. doi: 10.1189/JLB.2A0414-192R. Epub 2014 Jun 26.
HIV is known to subvert cellular machinery to enhance its replication. Recently, HIV has been reported to enhance TC renin expression. We hypothesized that HIV induces and maintains high renin expression to promote its own replication in TCs. Renin enhanced HIV replication in TCs in a dose-dependent manner. (P)RR-deficient TCs, as well as those lacking renin, displayed attenuated NF-κB activity and HIV replication. TCs treated with renin and Hpr displayed activation of the (P)RR-PLZF protein signaling cascade. Renin, HIV, and Hpr activated the PI3K pathway. Both renin and Hpr cleaved Agt (a renin substrate) to Ang I and also cleaved Gag polyproteins (protease substrate) to p24. Furthermore, aliskiren, a renin inhibitor, reduced renin- and Hpr-induced cleavage of Agt and Gag polyproteins. These findings indicate that renin contributes to HIV replication in TCs via the (P)RR-PLZF signaling cascade and through cleavage of the Gag polyproteins.
已知HIV会破坏细胞机制以增强其复制。最近，有报道称HIV会增强肾小管上皮细胞肾素的表达。我们推测，HIV诱导并维持高肾素表达以促进其在肾小管上皮细胞中的自身复制。肾素以剂量依赖的方式增强了HIV在肾小管上皮细胞中的复制。缺乏（脯氨酰）肾素受体（(P)RR）的肾小管上皮细胞以及缺乏肾素的细胞，其核因子κB（NF-κB）活性和HIV复制均减弱。用肾素和高血压蛋白原酶（Hpr）处理的肾小管上皮细胞显示出（脯氨酰）肾素受体-早幼粒细胞白血病锌指蛋白（(P)RR-PLZF）蛋白信号级联反应的激活。肾素、HIV和Hpr激活了磷脂酰肌醇-3激酶（PI3K）途径。肾素和Hpr都将血管紧张素原（Agt，一种肾素底物）裂解为血管紧张素I，并且还将Gag多聚蛋白（蛋白酶底物）裂解为p24。此外，肾素抑制剂阿利吉仑减少了肾素和Hpr诱导的Agt和Gag多聚蛋白的裂解。这些发现表明，肾素通过（脯氨酰）肾素受体-早幼粒细胞白血病锌指蛋白信号级联反应以及通过裂解Gag多聚蛋白，促进了HIV在肾小管上皮细胞中的复制。
