Physiological, cellular and molecular analysis of the role of mitochondrial dysfunction in people ageing with HIV

PhD Thesis90% of people living with HIV (PLWH) in the UK are now on treatment in the form of antiretroviral therapy (ART) and 87% of these PLWH are virally supressed. Due to the success of ART, PLWH are now living longer, and the mean age of PLWH in the UK is now 48 years (Public Health England, 2019). Despite successful ART, which has seen an increase in the quality of life for PLWH, some PLWH are living with an excess of frailty and reduction in physical function, as well as an increased susceptibility to acquiring age-related comorbidities (Guaraldi et al., 2011; Kooij et al., 2016; Desquilbet et al., 2007; Desquilbet et al., 2009; Brothers et al., 2017). This phenomenon is understood to be highly heterogeneic, but while many of the risk factors are known, the exact pathological basis remains poorly understood. This could be due to the fact that there has been a lack of studies investigating the cellular and molecular causes in functionally relevant tissues such as skeletal muscle. Mitochondrial dysfunction is one of the nine cellular and molecular hallmarks of ageing characterised by Lopez-Otin (Lopez-Otin et al., 2013). Mitochondrial defects are increased in HIV infection, despite viremia control as a result of ART (Payne et al., 2011), and PLWH have a high prevalence of mitochondrial-associated toxicities such as myopathy and peripheral neuropathy (Selvaraj et al., 2014; Cupler et al., 1995). These toxicities are strongly associated with nucleoside reverse-transcriptase inhibitors (NRTIs) such as zidovudine (AZT), zalcitabine (ddC), stavudine (d4T) and didanosine (ddI) (Dalakas et al., 1990; Arnaudo et al., 1991; Lim & Copeland, 2001; Lewis, 2003). However, mitochondrial dysfunction has also been demonstrated in individuals treated with newer antiretrovirals with a safter profile and low mitochondrial polymerase binding affinity, such as tenofovir disoproxil fumarate (TDF) (Samuels et al., 2017). Given the close association between mitochondrial dysfunction and ageing (Lopez-Otin et al., 2013), and mitochondrial dysfunction in HIV infection (Erlandson et al., 2013; Payne et al., 2011; Chou et al., 2013), it is more than plausible to suggest that mitochondrial dysfunction plays a significant role in the accelerated ageing seen in PLWH. Due to the fact that there is a lack of concise studies which have investigated the role of mitochondrial dysfunction in ageing PLWH, I employed a wide range of cellular and molecular techniques to study mitochondrial dysfunction and other age-related pathology in skeletal muscle of older PLWH. This was correlated with clinical and treatment data, as well as physical function and body composition. In addition, techniques established for the study of mitochondrial dysfunction in skeletal muscle were employed in a pilot study of mitochondrially-mediated renal disease in PLWH