Vlahakis S R, Bren G D, Algeciras-Schimnich A, Trushin S A, Schnepple D J, Badley A D
Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Clin Pharmacol Ther. 2007 Sep;82(3):294-9. doi: 10.1038/sj.clpt.6100140. Epub 2007 Mar 14.
Human immunodeficiency virus (HIV) infection results in excessive apoptosis of infected and uninfected cells, mediated by host and viral factors present in plasma. As HIV protease inhibitors (PIs) have intrinsic antiapoptotic properties, we questioned whether HIV PIs could block HIV-induced CD4+ T-cell death independent of their effects on HIV replication. We demonstrate that HIV PIs block the death of CD4+ T cells induced by HIV glycoprotein 120 (gp120), Vpr, and Tat, as well as host signals Fas ligand, tumor necrosis factor, and tumor necrosis factor-related apoptosis-inducing ligand. Using gp120/CXCR4 as a model, we show that the HIV PIs specifically block mitochondrial apoptosis signaling. Furthermore, HIV PIs inhibit CD4+ T-cell death induced by viruses with high-level resistance to PIs (P<0.01) and apoptosis induced by serum of HIV patients with known resistance to HIV PIs (P=0.01). Together, these results show that HIV PIs block CD4+ T-cell death and have a beneficial effect on CD4+ T-cell survival despite PI resistance.
人类免疫缺陷病毒（HIV）感染会导致受感染和未受感染细胞过度凋亡，这是由血浆中存在的宿主和病毒因子介导的。由于HIV蛋白酶抑制剂（PIs）具有内在的抗凋亡特性，我们质疑HIV PIs是否能够在不影响HIV复制的情况下阻断HIV诱导的CD4+ T细胞死亡。我们证明，HIV PIs可阻断由HIV糖蛋白120（gp120）、Vpr和Tat以及宿主信号Fas配体、肿瘤坏死因子和肿瘤坏死因子相关凋亡诱导配体诱导的CD4+ T细胞死亡。以gp120/CXCR4为模型，我们表明HIV PIs特异性地阻断线粒体凋亡信号传导。此外，HIV PIs可抑制对PIs具有高水平抗性的病毒诱导的CD4+ T细胞死亡（P<0.01）以及对HIV PIs具有已知抗性的HIV患者血清诱导的凋亡（P=0.01）。总之，这些结果表明，尽管存在PI抗性，HIV PIs仍可阻断CD4+ T细胞死亡并对CD4+ T细胞存活产生有益影响。
