Petit C, Mathez D, Barthelemy C, Leste-Lasserre T, Naviaux RK, Sonigo P, Leibowitch J; IAS Conference on HIV Pathogenesis and Treatment (2nd : 2003 : Paris, France).
Antivir Ther. 2003; 8 (Suppl.1): abstract no. 736.
Laboratoire Genetique des Virus, Institut Cochin, INSERM U567, CNRS UMR 8104, Universite Paris 5, France
OBJECTIVE: To investigate the impact of antiretroviral treatment on the mitochondrial DNA (mtDNA) content of peripheral blood monuclear cells (PBMCs) of HIV-1-infected patients. DESIGN: As absolute mtDNA copy numbers widely differed between individuals, we performed a longitudinal analysis, where the first historical patient's specimen was taken as baseline reference for relative comparison with the subsequent samples of that patient. METHODS: Mitochondrial and nuclear DNA quantitation per cell (beta-globin gene copies) both measured in Light Cycler real-time PCR on the whole DNA extracts of 361 serial live cryopreserved PBMCs collected in former trials and clinical follow-ups from 60 individuals with established or recently acquired HIV-1 infections before and under various antiviral combination therapy. RESULTS: mtDNA amounts were stable or increasing over years of natural HIV-1 infection in untreated patients (n=7), conformant with our finding of a lack of differences in mtDNA copy numbers in patients with either a long established or a recent lentiviral infection. Our quantitation system revealed significant changes in mtDNA copy number depending on the designated triple, quadruple or quintuple anti-HIV drug combinations. AZT+ddC+ritonavir and AZT+3TC+ddI regularly lead to mtDNA depletion in each of the treated patients whereas none of seven patients (and 35 cell specimens) under a d4T+3TC+indinavir combination showed any significant mtDNA content variations. In seven number of patients, mtDNA copy numbers were seen to return to pretreatment levels and/or above without any interruption of the priorly mt DNA depleting antiretroviral drug combination. CONCLUSION: Our assay system allowed for the detection of significant changes in the PBMC mtDNA content of HIV-1-infected patients taking antiretroviral drugs as reported in the litterature with other detection systems. Yet, mtDNA copy numbers could regularly be seen diminishing under some but not all nucleoside analogue-comprising drug combinations. This, plus the occasional finding that depleted mtDNA could spontaneously rise to baseline levels and over under uninterrupted treatment, should raise a note of caution about resorting to the PBMC mtDNA marker for the monitoring of anti-retroviral drug-related mitochondrial toxicities.
Publication Types:
Keywords:
- Anti-HIV Agents
- Antiviral Agents
- DNA, Mitochondrial
- HIV-1
- Humans
- Lamivudine
- Lymphocytes
- Stavudine
- Zalcitabine
- Zidovudine
Other ID:
UI: 102263015
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