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Subcutaneous fat tissue mitochondrial DNA depletion and adipose toxicity are strongly associated with nucleoside reverse transcriptase inhibitor (NRTI) therapy in HIV-infected patients

Hammond, E., Nolan, D., McKinnon, E., James, I. and Mallal, S. (2003) Subcutaneous fat tissue mitochondrial DNA depletion and adipose toxicity are strongly associated with nucleoside reverse transcriptase inhibitor (NRTI) therapy in HIV-infected patients. In: 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 8 - 11 July, Paris, France.

Abstract

OBJECTIVE/AIMS: To examine the pathophysiology of lipoatrophy in subcutaneous adipose tissue among Western Australian HIV cohort participants, focusing particularly on the potential role of nucleoside reverse transcriptase inhibitor (NRTI)-associated mitochondrial toxicity.

METHODS: We assessed adipocyte mitochondrial DNA (mtDNA) depletion in 92 subcutaneous fat biopsies from 70 HIV+ individuals and seven healthy controls. Confocal microscopy and immunohistochemistry were also performed on 26 longitudinal samples from 12 patients initiating or switching therapy, to assess changes in tissue morphology and mtDNA-encoded (COX I) and nuclear DNA (nDNA)-encoded (COX IV) mitochondrial proteins. Mixed effects models were utilized for data analysis, adjusting for multiple measurements in individuals.

RESULTS: Compared with HIV+ ART-naïve controls (n=24, 1288 copies/cell), median mtDNA copies/cell was reduced by 81% in stavudine recipients (n=28, 240 copies/cell, P<0.0001) and by 44% in zidovudine recipients (n=29, 726 copies/cell, P=0.006). Regimens without stavudine/ zidovudine (n=11, 1514 copies/cell) had similar mtDNA levels to controls (P>0.5). Significant differences between stavudine/lamivudine (n=23) and zidovudine/lamivudine (n=28) regimens were also found (P=0.002). Commencing/switching NRTI therapy was associated with significant changes in mtDNA levels within 2–12 months in sequential biopsy samples (n=19, 38 biopsies, P<0.01). No association between mtDNA levels and use of HIV protease inhibitors was detected (P=0.6), and CD4 T cell counts at the time of biopsy were also similar between NRTI treatment groups (P=0.9). Adipose tissue toxicity correlated with mtDNA depletion and was characterized by adipocyte pleiomorphism and mitochondrial proliferation, progressing to adipocyte loss with marked macrophage infiltration and disordered tissue architecture. Lipid-laden macrophages were detected indicating adipocyte apoptosis. In 4/7 biopsies with <300 mtDNA copies/cell, relative depletion of mtDNA-encoded protein COX I was detected. No significant differences were noted between PI-treated and PI-naïve biopsy samples.

CONCLUSION/DISCUSSION: These data indicate that adipocyte mtDNA depletion and mitochondrial toxicity are prominent in subcutaneous fat samples obtained from NRTI-treated individuals, providing a pathophysiological basis for the observed effects of NRTI choice and duration on lipoatrophy risk.

Publication Type: Conference Item
Murdoch Affiliation: Centre for Clinical Immunology and Biomedical Statistics
URI: http://researchrepository.murdoch.edu.au/id/eprint/15639
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