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Abstract
MITOCHONDRIAL DNA DEPLETION IN HIV+ PATIENTS WITH SYMPTOMATIC NUCLEOSIDE RELATED MITOCHONDRIAL TOXICITY.
COTE H, BRUMME Z, WYNHOVEN B, HARRIS M, CRAIB K, HARRIGAN P, O'SHAUGHNESSY M
Background: Mitochondrial toxicity (MT)-related adverse effects include acute lactic acidosis as well as chronic hyperlactatemia that may or may not be symptomatic. Nucleosides inhibit the polymerase ?, the enzyme that replicates mitochondrial DNA (mtDNA). We quantified mtDNA in longitudinal blood samples from individuals who interrupted antiretroviral therapy due to symptomatic MT.
Methods: Total DNA was extracted from buffycoats of 8 HIV+ eligible males. Samples were collected before, during and after therapy interruption (over an average of 18 months). Nuclear DNA (nDNA) and mtDNA were quantified by real-time PCR with fluorescent probes, and mtDNA/nDNA ratios were determined in 5-17 samples per patient. Standard curves were generated from a pool of DNA extracts from HIV- males (n=24), calibrated for its nuclear genome equivalent content.
Results: Symptoms of MT were associated with markedly low mtDNA that increased rapidly following discontinuation of therapy. Changes in mtDNA occurred more rapidly than changes in venous lactate levels. For the 8 patients, the mean of the lowest mtDNA/nDNA ratios while on therapy was significantly lower than the mean of the highest ratios off therapy (p<0.001). These were also significantly lower that the mean of ratios obtained for a group of HIV+/drug naïve male controls (n=26) (p<0.001). In the latter instance, the differences in the mtDNA/nDNA ratios were driven by the mtDNA content (p=0.013) of the extracts and not by variations in their nDNA (p=0.763).
Conclusions: We have developed a non-radioactive assay capable of detecting variations in blood mtDNA content associated with symptomatic nucleoside-related mitochondrial toxicity, and its improvement with therapy withdrawal. Further evaluation is required to determine the predictive value of this assay in the monitoring of patients on antiretrovirals.
The 1st. IAS Conference on HIV Pathogenesis and Treatment
Abstract no.
95
Suggested Citation
"COTEH, et al.
MITOCHONDRIAL DNA DEPLETION IN HIV+ PATIENTS WITH SYMPTOMATIC NUCLEOSIDE RELATED MITOCHONDRIAL TOXICITY..
Oral Presentation:
The 1st. IAS Conference on HIV Pathogenesis and Treatment
:
Abstract no.
95"
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