Buffet Marc, Schwarzinger Michaël, Amellal Bahia, Gourlain Karine, Bui Patrick, Prévot Marianne, Deleuze Jean, Morini Jean-Pierre, Gorin Isabelle, Calvez Vincent, Dupin Nicolas
Service de Dermatologie, Pavillon Tarnier, Hôpital Cochin, Université René Descartes, Paris V, France.
J Clin Virol. 2005 May;33(1):60-4. doi: 10.1016/j.jcv.2004.09.027.
NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion. Determinants of cellular mtDNA copy number from HIV-infected patients receiving HAART and HIV-seronegative controls were investigated from subcutaneous fat samples, and relation with antiretroviral regimen was studied.
HIV-infected patients receiving HAART (n = 50), HIV-infected patients not currently under HAART regimen (n = 2) and HIV-seronegative controls (n = 9) of similar age and BMI were enrolled prospectively when undergoing Coleman's lipostructure for correction of facial lipoatrophy or plastic surgery, respectively. After centrifugation, abdominal fat tissue was collected and stored at -80 degrees C. MtDNA analysis was blindly performed after a total DNA extraction from adipose tissue, followed by a real-time PCR quantification. The log of mtDNA copies/cell in adipose tissue [log(DNA)] was compared between groups by means of analysis of variance.
The log(DNA) in adipose tissue of HIV-infected patients was significantly lower than in the HIV-seronegative control group (P < 0.0001). In HIV-infected patients, log(DNA) was significantly reduced in the 50 NRTI-treated patients (P < 0.01), but not when considering mtDNA level according to the use of PI or NNRTI in current HAART regimen. In NRTI-treated patients, only stavudine (n = 20) and didanosine (n=14) were significantly and independently associated with reduced mtDNA level (P < 0.0001 and <0.05, respectively). Currently stavudine or didanosine-treated patients had a significant reduced mtDNA level compared to past users (P < 0.0001 and <0.05, respectively). Other clinical, biological, and immuno-virological variables than NRTI did not correlate significantly to adipocyte mtDNA level.
This study supports that current treatment by NRTI is a main determinant of mtDNA depletion in adipose tissue of HIV-seropositive patients with peripheral fat wasting. Stavudine or didanosine current intake is significantly associated with mtDNA depletion in vivo, that could be reversible after the discontinuation of these molecules, when considering mtDNA level according to current use versus past use of these molecules.
核苷类逆转录酶抑制剂（NRTI）引起的宿主毒性被认为与细胞线粒体DNA（mtDNA）耗竭有关。我们从皮下脂肪样本中研究了接受高效抗逆转录病毒治疗（HAART）的HIV感染患者和HIV血清学阴性对照者的细胞mtDNA拷贝数的决定因素，并研究了其与抗逆转录病毒治疗方案的关系。
前瞻性纳入了年龄和体重指数（BMI）相似的接受HAART的HIV感染患者（n = 50）、目前未接受HAART治疗的HIV感染患者（n = 2）以及HIV血清学阴性对照者（n = 9），他们分别在接受科尔曼面部脂肪萎缩矫正术或整形手术时入组。离心后，收集腹部脂肪组织并储存在-80℃。从脂肪组织中提取总DNA后，进行盲法mtDNA分析，随后进行实时PCR定量。通过方差分析比较各组脂肪组织中mtDNA拷贝数/细胞的对数[log(DNA)]。
HIV感染患者脂肪组织中的log(DNA)显著低于HIV血清学阴性对照组（P < 0.0001）。在HIV感染患者中，50例接受NRTI治疗的患者log(DNA)显著降低（P < 0.01），但根据目前HAART治疗方案中蛋白酶抑制剂（PI）或非核苷类逆转录酶抑制剂（NNRTI）的使用情况考虑mtDNA水平时则不然。在接受NRTI治疗的患者中，只有司他夫定（n = 20）和去羟肌苷（n = 14）与mtDNA水平降低显著且独立相关（分别为P < 0.0001和<0.05）。目前接受司他夫定或去羟肌苷治疗的患者与过去使用者相比，mtDNA水平显著降低（分别为P < 0.0001和<0.05）。除NRTI外的其他临床、生物学和免疫病毒学变量与脂肪细胞mtDNA水平无显著相关性。
本研究支持目前NRTI治疗是外周脂肪消耗的HIV血清阳性患者脂肪组织中mtDNA耗竭的主要决定因素。目前服用司他夫定或去羟肌苷与体内mtDNA耗竭显著相关，根据这些分子的当前使用情况与过去使用情况考虑mtDNA水平时，停用这些分子后可能是可逆的。
