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Title: HIV infection, nucleoside analogue therapy and somatic mitochondrial DNA mutation : implications for ageing?
Author: Payne, Brendan Alexander Ingleby
ISNI:       0000 0004 5360 8722
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2014
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It has been hypothesised that patients with long-term treated HIV infection may exhibit features of accelerated physiological ageing. Given previously established links between, a) anti-retroviral therapy and mitochondrial DNA (mtDNA), and b) mtDNA and ageing, I hypothesised that anti-retroviral therapy may lead to the accumulation of mtDNA mutations, in an acceleration of the molecular process seen in normal human ageing. Using a combination of single cell molecular analyses and ultra-deep sequencing (UDS), I demonstrated that HIV-infected patients with prior exposure to polymerase (pol) γ inhibiting NRTI (nucleoside analogue reverse transcriptase inhibitor) therapy show increased accumulation of somatic mtDNA mutations within cells, in a pattern similar to that seen much later in life due to normal ageing. Empirical data and in silico modelling suggested this is likely to be mediated by the accelerated clonal expansion of pre-existing (age-associated) mtDNA mutations, rather than by increased mutagenesis. I went on to further develop the UDS methodology, to explore more fundamental questions about the characteristics of mtDNA mutations in ageing, health and disease. In so doing, I showed that low-level mtDNA heteroplasmic mutation appears to be universal, and that many ostensibly somatic mutations may in fact have been maternally transmitted at very low levels. I explored the utility of serum FGF-21 (fibroblast growth factor 21) and phosphorus magnetic resonance spectroscopy (31P-MRS) as non-invasive measures of muscle mitochondrial dysfunction in anti-retroviral treated patients. Both showed significant abnormalities, although neither proved sensitive or specific in my patient group. Finally I explored the frequency and severity of fatigue in contemporary HIV-infected patients, showing that half of all patients have excessive fatigue despite good immune function and suppressed HIV viraemia. Patients with prior exposure to pol γ inhibiting NRTIs were almost universally fatigued, suggesting that persistent mitochondrial dysfunction due to accumulated mtDNA mutations may be important in driving fatigue in this patient group.
Supervisor: Not available Sponsor: Medical Research Council (MRC) ; British Infection Association (BIA) ; National Institute for Health Research (NIHR), Biomedical Research Centre for Ageing and Age-Related Disease ; Newcastle Healthcare Charity
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available