Mitochondrial Toxicity Studied With the PBMC of Children From the Chinese National Pediatric Highly Active Antiretroviral Therapy Cohort

PLoS One. 2013;8(2):e57223. doi: 10.1371/journal.pone.0057223. Epub 2013 Feb 27.

Abstract

As the backbone of highly active antiretroviral therapy (HAART), nucleoside reverse transcriptase inhibitors (NRTIs) have effectively improved outcomes for HIV-infected patients. However, long-term treatment with NRTIs can cause a series of pathologies associated with mitochondrial toxicity. To date, the status and mechanism of mitochondrial toxicity induced by NRTIs are still not clear, especially in HIV-infected children. As part of the national pediatric HAART program in China, our study focused on mitochondrial toxicity and its potential mechanism in HIV-1-infected children who were divided into two groups based on their duration of treatment with NRTIs: one group received treatment for less than 36 months and one group was treated for 36 to 72 months. The control group comprised age-matched non-HIV-infected children. Blood lactic acid and ATP levels in peripheral blood mononuclear cells (PBMCs) were measured to evaluate mitochondrial function, and mtDNA copies and mutations in PBMCs were determined for detecting mtDNA lesions. Simultaneously, TK2 and P53R2 gene expression in PBMC was measured. As compared with the control group, blood lactic acid levels in both NRTI treatment groups were significantly higher, whereas ATP levels and mtDNA mutation rates in PBMCs did not differ between the control and the two NRTI treatment groups. Both NRTI treatment groups exhibited significant mtDNA loss. N Moreover, we found that P53R2 mRNA expression and protein levels were significantly reduced in both treatment groups and that TK2 mRNA expression and protein levels were induced in the long-term NRTI treatment group. These results suggest that mitochondrial toxicity occurs in long-term HAART patients and that P53R2 and TK2 levels in PBMCs are useful biomarkers for detecting mitochondrial toxicity in patients on long-term treatment with NRTIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / blood
  • Adolescent
  • Blotting, Western
  • Child
  • Child, Preschool
  • China
  • DNA, Mitochondrial / analysis
  • DNA, Mitochondrial / genetics
  • Female
  • HIV Infections / drug therapy*
  • Humans
  • Lactic Acid / blood
  • Male
  • Mitochondria / drug effects*
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Mutation
  • Oxidative Phosphorylation
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Reverse Transcriptase Inhibitors / toxicity*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • DNA, Mitochondrial
  • Reverse Transcriptase Inhibitors
  • Lactic Acid
  • Adenosine Triphosphate

Grant support

This work is sponsored by Twelve-fifth Key Science and Technology Five Year Plan of China (2012ZX10001003-003-002, 2012ZX10001004-002 and 2012BAI15B08) and the National Natural Science Foundation of China (81272266 and 30910103915). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.