Karamchand Leshern, Dawood Halima, Chuturgoon Anil A
Department of Medical Biochemistry, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
J Acquir Immune Defic Syndr. 2008 Aug 1;48(4):381-8. doi: 10.1097/QAI.0b013e3181799662.
Efavirenz (EFV) and nevirapine (NVP), unlike nucleoside reverse transcriptase inhibitor drugs, do not inhibit mitochondrial (mt) polymerase gamma (Pol-gamma), although EFV has been shown to induce mt depolarization (Deltapsim) in vitro at supratherapeutic concentrations. However, the capacity of nonnucleoside reverse transcriptase inhibitor drugs to induce mt toxicity in vivo remains undetermined.
To determine the influence of EFV and NVP on peripheral lymphocyte mt transmembrane potential (Deltapsim) and apoptosis in HIV-1-infected patients treated with these nonnucleoside reverse transcriptase inhibitors.
Thirty-two HIV-1-infected patients on highly active antiretroviral therapy (HAART) between 4 and 24 months (12 on EFV, 20 on NVP) and 16 HAART-naive HIV-1-infected patients were enrolled into this study. All participants were black South African patients. Spontaneous peripheral lymphocyte apoptosis and Deltapsim were measured ex vivo by flow cytometry for all patients.
: CD4 T-helper apoptosis for the EFV and NVP cohorts was 19.38% +/- 2.62% and 23.35% +/- 1.51% (mean +/- SEM), respectively, whereas total lymphocyte Deltapsim was 27.25% +/- 5.05% and 17.04% +/- 2.98%, respectively. Both parameters for each cohort were significantly lower (P < 0.05) than that of the HAART-naive patients. The NVP cohort exhibited both a significant time-dependent increase in peripheral lymphocyte Deltapsim (P = 0.038) and correlation between T-helper apoptosis and Deltapsim (P = 0.0005). These trends were not observed in the EFV cohort.
This study provides evidence that both EFV and NVP induce peripheral lymphocyte Deltapsim in HIV-1-infected patients on nonnucleoside reverse transcriptase inhibitor-based HAART, which in the case of NVP is sufficient to induce the apoptosis cascade.
与核苷类逆转录酶抑制剂不同，依非韦伦（EFV）和奈韦拉平（NVP）不抑制线粒体（mt）聚合酶γ（Pol-γ），尽管在体外超治疗浓度下依非韦伦已被证明可诱导线粒体去极化（Δψm）。然而，非核苷类逆转录酶抑制剂药物在体内诱导线粒体毒性的能力仍未确定。
确定依非韦伦和奈韦拉平对接受这些非核苷类逆转录酶抑制剂治疗的HIV-1感染患者外周淋巴细胞线粒体跨膜电位（Δψm）和细胞凋亡的影响。
32例接受高效抗逆转录病毒治疗（HAART）4至24个月的HIV-1感染患者（12例使用依非韦伦，20例使用奈韦拉平）和16例未接受过HAART的HIV-1感染患者纳入本研究。所有参与者均为南非黑人患者。通过流式细胞术对所有患者的外周淋巴细胞自发凋亡和Δψm进行离体检测。
依非韦伦组和奈韦拉平组的CD4辅助性T细胞凋亡率分别为19.38%±2.62%和23.35%±1.51%（平均值±标准误），而总淋巴细胞Δψm分别为27.25%±5.05%和17.04%±2.98%。每个组的这两个参数均显著低于未接受过HAART的患者（P<0.05）。奈韦拉平组外周淋巴细胞Δψm呈现出显著的时间依赖性增加（P = 0.038），且辅助性T细胞凋亡与Δψm之间存在相关性（P = 0.0005）。在依非韦伦组未观察到这些趋势。
本研究提供了证据表明，在基于非核苷类逆转录酶抑制剂的HAART治疗的HIV-1感染患者中，依非韦伦和奈韦拉平均可诱导外周淋巴细胞Δψm，就奈韦拉平而言，这足以诱导细胞凋亡级联反应。
