Schweinsburg Brian C, Taylor Michael J, Alhassoon Omar M, Gonzalez Raul, Brown Gregory G, Ellis Ronald J, Letendre Scott, Videen John S, McCutchan J Allen, Patterson Thomas L, Grant Igor
VA San Diego Healthcare System, San Diego, California 92103, USA.
J Neurovirol. 2005 Aug;11(4):356-64. doi: 10.1080/13550280591002342.
Nucleoside reverse transcriptase inhibitors (NRTIs) suppress human immunodeficiency virus (HIV) replication, but are often associated with mitochondrial toxicity. Although well studied outside of the central nervous system, no investigation has examined the effects of these drugs on brain mitochondria of individuals living with HIV. The authors used proton magnetic resonance spectroscopy to evaluate NRTI-related changes in brain mitochondria. N-acetylaspartate (NAA; sensitive to alterations in mitochondrial integrity) was measured in frontal lobe white and gray matter of 18 HIV+ individuals taking didanosine and/or stavudine (two NRTIs likely to cause mitochondrial toxicity), 14 HIV+ individuals taking zidovudine and lamivudine, 16 HIV+ individuals not currently taking antiretrovirals, and 17 HIV- controls. The HIV+ groups were comparable on demographic measures, estimates of illness severity, and estimated length of HIV infection. Those taking didanosine and/or stavudine had a significant 11.4% decrease in concentrations of frontal white matter NAA compared to HIV- controls, whereas NAA levels of the other HIV+ groups were intermediate. Group differences in metabolites were not found in frontal gray matter. Lower levels of frontal white matter NAA were associated with longer periods of didanosine and/or stavudine treatment (r = -.41, P = .06). Levels of NAA were not related to length of zidovudine/lamivudine treatment (r = -.04, P = .44). Furthermore, taking more than one of stavudine, didanosine, and abacavir increased the likelihood of having reduced NAA. The results are consistent with previous studies finding HIV-related changes in neuronal integrity. However, because NRTIs can injure mitochondria, we propose that the observed reductions in NAA in individuals taking didanosine and/or stavudine may be the result of depleted brain mitochondria and/or alterations in cellular respiration. Measurement of brain metabolites sensitive to impairments in energy metabolism, including NAA, may aid in early detection of subclinical NRTI-mediated mitochondrial toxicity.
核苷类逆转录酶抑制剂（NRTIs）可抑制人类免疫缺陷病毒（HIV）复制，但常与线粒体毒性相关。尽管在中枢神经系统之外已对其进行了充分研究，但尚无研究考察这些药物对HIV感染者脑线粒体的影响。作者使用质子磁共振波谱来评估与NRTIs相关的脑线粒体变化。在18名服用去羟肌苷和/或司他夫定（两种可能导致线粒体毒性的NRTIs）的HIV阳性个体、14名服用齐多夫定和拉米夫定的HIV阳性个体、16名目前未服用抗逆转录病毒药物的HIV阳性个体以及17名HIV阴性对照者的额叶白质和灰质中测量了N-乙酰天门冬氨酸（NAA；对线粒体完整性改变敏感）。HIV阳性组在人口统计学指标、疾病严重程度估计以及HIV感染估计时长方面具有可比性。与HIV阴性对照者相比，服用去羟肌苷和/或司他夫定的个体额叶白质NAA浓度显著降低了11.4%，而其他HIV阳性组的NAA水平处于中间值。在额叶灰质中未发现代谢物的组间差异。额叶白质NAA水平较低与去羟肌苷和/或司他夫定治疗时间较长相关（r = -0.41，P = 0.06）。NAA水平与齐多夫定/拉米夫定治疗时长无关（r = -0.04，P = 0.44）。此外，同时服用司他夫定、去羟肌苷和阿巴卡韦中的一种以上会增加NAA降低的可能性。这些结果与之前发现HIV相关神经元完整性变化的研究一致。然而，由于NRTIs会损伤线粒体，我们认为在服用去羟肌苷和/或司他夫定的个体中观察到的NAA降低可能是脑线粒体耗竭和/或细胞呼吸改变的结果。测量对能量代谢受损敏感的脑代谢物，包括NAA，可能有助于早期发现亚临床NRTI介导的线粒体毒性。
