title: In vivo mitochondrial function in HIV-infected persons treated with contemporary anti-retroviral therapy: a magnetic resonance spectroscopy study.
abstract: Modern anti-retroviral therapy is highly effective at suppressing viral replication and restoring immune function in HIV-infected persons. However, such individuals show reduced physiological performance and increased frailty compared with age-matched uninfected persons. Contemporary anti-retroviral therapy is thought to be largely free from neuromuscular complications, whereas several anti-retroviral drugs previously in common usage have been associated with mitochondrial toxicity. It has recently been established that patients with prior exposure to such drugs exhibit irreversible cellular and molecular mitochondrial defects. However the functional significance of such damage remains unknown. Here we use phosphorus magnetic resonance spectroscopy ((31)P-MRS) to measure in vivo muscle mitochondrial oxidative function, in patients treated with contemporary anti-retroviral therapy, and compare with biopsy findings (cytochrome c oxidase (COX) histochemistry). We show that dynamic oxidative function (post-exertional ATP (adenosine triphosphate) resynthesis) was largely maintained in the face of mild to moderate COX defects (affecting up to ∼10% of fibers): τ½ ADP (half-life of adenosine diphosphate clearance), HIV-infected 22.1±9.9 s, HIV-uninfected 18.8±4.4 s, p = 0.09. In contrast, HIV-infected patients had a significant derangement of resting state ATP metabolism compared with controls: ADP/ATP ratio, HIV-infected 1.24±0.08×10(-3), HIV-uninfected 1.16±0.05×10(-3), p = 0.001. These observations are broadly reassuring in that they suggest that in vivo mitochondrial function in patients on contemporary anti-retroviral therapy is largely maintained at the whole organ level, despite histochemical (COX) defects within individual cells. Basal energy requirements may nevertheless be increased.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom ; Department of Infection and Tropical Medicine, Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom.
authors.forename: Brendan A I
authors.initials: BA
authors.lastname: Payne
authors.affiliation: Newcastle Magnetic Resonance Centre, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
authors.forename: Kieren G
authors.initials: KG
authors.lastname: Hollingsworth
authors.affiliation: Department of Infectious Diseases, North Manchester General Hospital, Manchester, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Baxter
authors.affiliation: Department of Infectious Diseases, North Manchester General Hospital, Manchester, United Kingdom.
authors.forename: Edmund
authors.initials: E
authors.lastname: Wilkins
authors.affiliation: Manchester Centre for Sexual Health, Manchester Royal Infirmary, Manchester, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lee
authors.affiliation: Department of Infection and Tropical Medicine, Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom.
authors.forename: D Ashley
authors.initials: DA
authors.lastname: Price
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Trenell
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D019562:Viral Load
chemical_list: D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV