Elahi Shokrollah, Weiss Robert H, Merani Shahzma
aDepartment of Dentistry bDepartment of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada cDivision of Nephrology and Cancer Center, University of California, Davis dSacramento VA Medical Center, Sacramento, California, USA.
AIDS. 2016 Jan;30(2):171-83. doi: 10.1097/QAD.0000000000000917.
Antigen persistence due to HIV is a major source of inflammation and substantial immune activation, both of which are linked to accelerated aging. This illustrates the need to reduce immune activation in these patients and subsequently decrease the risk of cardiovascular diseases and other non-AIDS-defining comorbidities.
CD4 T cells were infected with HIV-1 isolates in the presence or absence of atorvastatin (0.25 to 1 μg/ml) for 24-48 h. Atorvastatin-induced anti-inflammatory functions and anti-viral replication were measured in vitro.
Atorvastatin, a lipid-lowering medication, exerted a broad spectrum of anti-inflammatory functions by reducing T-cell immune activation markers (e.g. CD38, HLA-DR and Ki67), lowering HIV-1 co-receptor CCR-5, and decreasing proliferative capabilities of CD4 T cells in vitro. In contrast, atorvastatin expanded regulatory T cells (Tregs) and upregulated the expression of T-cell immunoglobulin and ITIM domain (TIGIT), which enhanced the suppressive activity of Tregs. Furthermore, atorvastatin upregulated the cyclin-dependent kinase inhibitor p21, which is also known as cip-1 and waf-1, in the CD4 T cells. Upregulation of p21 in CD4 T cells rendered them less susceptible to HIV-1 infection and replication whereas siRNA-mediated p21 depletion and/or p21 selective inhibitor rescued viral replication. Interestingly, atorvastatin reduced HIV infection in both rested and phytohemagglutinin-activated CD4 T cells in vitro. Finally, atorvastatin mediated p21 upregulation occurred via mevalonate pathway, but independent of p53.
The results demonstrate a novel mechanism by which atorvastatin induced resistance of CD4 T cells to HIV-1 infection via p21 upregulation and suggest that statins may hold particular promise for some HIV-infected individuals.
HIV导致的抗原持续存在是炎症和大量免疫激活的主要来源，这两者都与加速衰老有关。这表明有必要降低这些患者的免疫激活水平，进而降低心血管疾病和其他非艾滋病定义的合并症的风险。
在存在或不存在阿托伐他汀（0.25至1μg/ml）的情况下，用HIV-1分离株感染CD4 T细胞24 - 48小时。在体外测量阿托伐他汀诱导的抗炎功能和抗病毒复制。
阿托伐他汀是一种降脂药物，通过降低T细胞免疫激活标志物（如CD38、HLA-DR和Ki67）、降低HIV-1共受体CCR-5以及在体外降低CD4 T细胞的增殖能力，发挥广泛的抗炎功能。相比之下，阿托伐他汀可扩增调节性T细胞（Tregs）并上调T细胞免疫球蛋白和ITIM结构域（TIGIT）的表达，从而增强Tregs的抑制活性。此外，阿托伐他汀上调了CD4 T细胞中细胞周期蛋白依赖性激酶抑制剂p21（也称为cip-1和waf-1）。CD4 T细胞中p21的上调使其对HIV-1感染和复制的敏感性降低，而siRNA介导的p21缺失和/或p21选择性抑制剂可挽救病毒复制。有趣的是，阿托伐他汀在体外降低了静息和植物血凝素激活的CD4 T细胞中的HIV感染。最后，阿托伐他汀介导的p21上调通过甲羟戊酸途径发生，但独立于p53。
结果证明了一种新机制，即阿托伐他汀通过上调p21诱导CD4 T细胞对HIV-1感染产生抗性，并表明他汀类药物可能对某些HIV感染个体具有特殊前景。
