Mitochondrial dysfunction and anti-retroviral therapy.

In this week’s WCMR ‘Research in Progress’ meeting we heard from Matthew Hunt, who told us about his PhD project investigating mitochondrial dysfunction and contemporary anti-retrovial therapy. Here, Matthew tells us why this is important.

HIV infection should now be viewed as a chronic manageable disease, with 87% of people living with HIV in the UK receiving effective treatment in the form of anti-retroviral therapy (ART).

ART has been so successful in turning HIV from what was once a deadly disease into a manageable condition that there is now almost zero risk of the disease being transmitted from someone on effective ART. ART does have its downside, though, as it is associated with faster biological ageing. This is characterised by a reduction in physical function and an increased prevalence of frailty, age-related diseases and mortality – when compared to the age-matched HIV negative population.

One of the key mediators of this accelerated ageing are mitochondria. Early ART drugs, known as nucleotide reverse transcriptase inhibitors (NRTI), have been shown to cause mitochondrial dysfunction by inhibiting polymerase gamma, an enzyme that is responsible for the process of mitochondrial DNA (mtDNA) replication. When polymerase gamma is inhibited, there is a reduction in the amount of mtDNA synthesised and an increased risk of mtDNA mutations, both of which lead to a range of mitochondrial defects. Most significantly, these defects mean that less energy is produced by the mitochondria.

Over the years, most of the older ‘mitochondrially toxic’ NRTIs have been discontinued and replaced with contemporary NRTIs which do not inhibit polymerase gamma. However, there have been few studies investigating whether these newer NRTIs cause mitochondrial defects in functionally relevant tissues, such as skeletal muscle. This is what my research project aims to investigate.

Through a range of cellular and molecular work, which includes looking at energy production in muscle from people living with HIV with different ART treatment histories, we have demonstrated for the first time that newer ‘contemporary’ NRTIs can cause mitochondrial defects. Our future work will include investigating how much of an impact these mitochondrial defects have on accelerated ageing in those living with HIV.