López Sònia, Negredo Eugènia, Garrabou Glòria, Puig Jordi, Ruiz Lidia, Sanjurjo Eduard, Ramos Xavier, Infante Ana B, Casademont Jordi, Cardellach Francesc, Clotet Bonaventura, Miró Oscar
Mitochondrial Research Laboratory, Muscle Research Unit, Internal Medicine Department, Hospital Clínic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain.
AIDS Res Hum Retroviruses. 2006 Jan;22(1):33-9. doi: 10.1089/aid.2006.22.33.
Tenofovir disoproxil fumarate (TDF) has been reported to be free of adverse effects on mitochondria. We evaluate the effects of the introduction of TDF in a didanosine (ddI)-based highly active antiretroviral therapy (HAART) on mitochondrial DNA (mtDNA) content, mitochondrial mass (MM), and cytochrome c oxidase (COX) activity of the oxidative phosphorylation (OXPHOS) system over a 12-month period. Forty-four asymptomatic HIV patients with undetectable viral load receiving a ddI-based HAART were recruited and switched to ddI plus TDF (ddI + TDF) and nevirapine (n = 22) or maintained with the same baseline ddIbased HAART scheme (n = 22). Peripheral blood mononuclear cells were obtained at 0, 6, and 12 months. COX activity and MM were determined by spectrophotometry and the mtDNA content by quantitative realtime PCR. The mtDNA content showed a progressive decrease over the 12-month period of the study for the two groups with respect to baseline, with such a decrease statistically significant only in the ddI + TDF group (55% decrease, p < 0.001). In addition, the decrease of mtDNA content over time was statistically different between both groups (p < 0.001). Consistently, MM and COX activity decreased significantly at 12 months with respect to baseline only in the ddI < TDF group (28% decrease for MM, p < 0.05; 47% decrease for COX activity, p < 0.001). We conclude that switching to a HAART regimen containing ddI + TDF is associated with evolutive mitochondrial damage expressed as mtDNA depletion, loss of MM, and decrease in COX efficiency. The particular relevance of either ddI, TDF, or any interaction between them in such a mitochondrial dysfunction remains to be established.
据报道，替诺福韦酯（TDF）对线粒体无不良影响。我们评估了在基于去羟肌苷（ddI）的高效抗逆转录病毒疗法（HAART）中引入TDF，在12个月期间对线粒体DNA（mtDNA）含量、线粒体质量（MM）以及氧化磷酸化（OXPHOS）系统的细胞色素c氧化酶（COX）活性的影响。招募了44名接受基于ddI的HAART且病毒载量不可检测的无症状HIV患者，将其转换为ddI加TDF（ddI + TDF）和奈韦拉平（n = 22），或维持相同的基于ddI的基线HAART方案（n = 22）。在第0、6和12个月获取外周血单个核细胞。通过分光光度法测定COX活性和MM，通过定量实时PCR测定mtDNA含量。在研究的12个月期间，两组的mtDNA含量相对于基线均呈逐渐下降，仅在ddI + TDF组这种下降具有统计学意义（下降55%，p < 0.001）。此外，两组之间mtDNA含量随时间的下降在统计学上存在差异（p < 0.001）。同样，仅在ddI + TDF组中，MM和COX活性在12个月时相对于基线显著下降（MM下降28%，p < 0.05；COX活性下降47%，p < 0.001）。我们得出结论，转换为包含ddI + TDF的HAART方案与以mtDNA耗竭、MM丧失和COX效率降低为表现的进行性线粒体损伤相关。ddI、TDF或它们之间的任何相互作用在这种线粒体功能障碍中的具体相关性仍有待确定。
