In vivo mitochondrial function in HIV-infected persons treated with contemporary anti-retroviral therapy: a magnetic resonance spectroscopy study
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...
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| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0084678 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0084678</identifier><identifier>PMID: 24409305</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine diphosphate ; Adenosine triphosphate ; Adenosine Triphosphate - metabolism ; Aged ; Ambulatory care ; Antiretroviral agents ; Antiretroviral drugs ; Antiretroviral Therapy, Highly Active ; ATP ; ATP (Adenosine triphosphate) ; ATPases ; Biocompatibility ; Biopsy ; CD4 Lymphocyte Count ; Chemistry ; Complications ; Cytochrome ; Cytochrome-c oxidase ; Defects ; Deoxyribonucleic acid ; DNA ; Drugs ; Electron Transport Complex IV - metabolism ; Energy requirements ; Exercise ; Female ; Genomes ; Histochemistry ; Histology ; HIV ; HIV infections ; HIV Infections - drug therapy ; HIV Infections - immunology ; HIV Infections - metabolism ; HIV Infections - virology ; HIV patients ; Hospitals ; Human immunodeficiency virus ; Humans ; Immune clearance ; Immune response ; Immunosuppressive agents ; Infections ; Infectious diseases ; Magnetic resonance ; Magnetic Resonance Spectroscopy ; Male ; Medicine ; Metabolism ; Metabolites ; Middle Aged ; Mitochondria ; Mitochondria - metabolism ; Mitochondria, Muscle - metabolism ; Mitochondrial DNA ; Muscle proteins ; Muscle, Skeletal - metabolism ; Muscles ; Musculoskeletal system ; Mutation ; Neuromuscular diseases ; Nuclear magnetic resonance spectroscopy ; Oxidases ; Patients ; Phosphorus ; Phosphorylation ; Physical fitness ; Physiological aspects ; Resonance ; Signal transduction ; Spectroscopy ; Spectrum analysis ; Studies ; Therapy ; Toxicity ; User interface ; Viral Load</subject><ispartof>PloS one, 2014-01, Vol.9 (1), p.e84678-e84678</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Payne et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Payne et al 2014 Payne et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-7b795b74731a757a8a9fd72b2ae346f1837af2b4513fa2c62757334d3336b4c83</citedby><cites>FETCH-LOGICAL-c692t-7b795b74731a757a8a9fd72b2ae346f1837af2b4513fa2c62757334d3336b4c83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883680/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883680/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79472,79473</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24409305$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Wilkinson, Robert J.</contributor><creatorcontrib>Payne, Brendan A I</creatorcontrib><creatorcontrib>Hollingsworth, Kieren G</creatorcontrib><creatorcontrib>Baxter, Joanne</creatorcontrib><creatorcontrib>Wilkins, Edmund</creatorcontrib><creatorcontrib>Lee, Vincent</creatorcontrib><creatorcontrib>Price, D Ashley</creatorcontrib><creatorcontrib>Trenell, Michael</creatorcontrib><creatorcontrib>Chinnery, Patrick F</creatorcontrib><title>In vivo mitochondrial function in HIV-infected persons treated with contemporary anti-retroviral therapy: a magnetic resonance spectroscopy study</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Adenosine diphosphate</subject><subject>Adenosine triphosphate</subject><subject>Adenosine Triphosphate - metabolism</subject><subject>Aged</subject><subject>Ambulatory care</subject><subject>Antiretroviral agents</subject><subject>Antiretroviral drugs</subject><subject>Antiretroviral Therapy, Highly Active</subject><subject>ATP</subject><subject>ATP (Adenosine triphosphate)</subject><subject>ATPases</subject><subject>Biocompatibility</subject><subject>Biopsy</subject><subject>CD4 Lymphocyte Count</subject><subject>Chemistry</subject><subject>Complications</subject><subject>Cytochrome</subject><subject>Cytochrome-c oxidase</subject><subject>Defects</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drugs</subject><subject>Electron Transport Complex IV - metabolism</subject><subject>Energy requirements</subject><subject>Exercise</subject><subject>Female</subject><subject>Genomes</subject><subject>Histochemistry</subject><subject>Histology</subject><subject>HIV</subject><subject>HIV infections</subject><subject>HIV Infections - drug therapy</subject><subject>HIV Infections - immunology</subject><subject>HIV Infections - metabolism</subject><subject>HIV Infections - virology</subject><subject>HIV patients</subject><subject>Hospitals</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Immune clearance</subject><subject>Immune response</subject><subject>Immunosuppressive agents</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Magnetic resonance</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Middle Aged</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria, Muscle - metabolism</subject><subject>Mitochondrial DNA</subject><subject>Muscle proteins</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscles</subject><subject>Musculoskeletal system</subject><subject>Mutation</subject><subject>Neuromuscular diseases</subject><subject>Nuclear magnetic resonance spectroscopy</subject><subject>Oxidases</subject><subject>Patients</subject><subject>Phosphorus</subject><subject>Phosphorylation</subject><subject>Physical fitness</subject><subject>Physiological aspects</subject><subject>Resonance</subject><subject>Signal transduction</subject><subject>Spectroscopy</subject><subject>Spectrum analysis</subject><subject>Studies</subject><subject>Therapy</subject><subject>Toxicity</subject><subject>User interface</subject><subject>Viral 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One</addtitle><date>2014-01-07</date><risdate>2014</risdate><volume>9</volume><issue>1</issue><spage>e84678</spage><epage>e84678</epage><pages>e84678-e84678</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24409305</pmid><doi>10.1371/journal.pone.0084678</doi><tpages>e84678</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-01, Vol.9 (1), p.e84678-e84678 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1475119775 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenosine diphosphate Adenosine triphosphate Adenosine Triphosphate - metabolism Aged Ambulatory care Antiretroviral agents Antiretroviral drugs Antiretroviral Therapy, Highly Active ATP ATP (Adenosine triphosphate) ATPases Biocompatibility Biopsy CD4 Lymphocyte Count Chemistry Complications Cytochrome Cytochrome-c oxidase Defects Deoxyribonucleic acid DNA Drugs Electron Transport Complex IV - metabolism Energy requirements Exercise Female Genomes Histochemistry Histology HIV HIV infections HIV Infections - drug therapy HIV Infections - immunology HIV Infections - metabolism HIV Infections - virology HIV patients Hospitals Human immunodeficiency virus Humans Immune clearance Immune response Immunosuppressive agents Infections Infectious diseases Magnetic resonance Magnetic Resonance Spectroscopy Male Medicine Metabolism Metabolites Middle Aged Mitochondria Mitochondria - metabolism Mitochondria, Muscle - metabolism Mitochondrial DNA Muscle proteins Muscle, Skeletal - metabolism Muscles Musculoskeletal system Mutation Neuromuscular diseases Nuclear magnetic resonance spectroscopy Oxidases Patients Phosphorus Phosphorylation Physical fitness Physiological aspects Resonance Signal transduction Spectroscopy Spectrum analysis Studies Therapy Toxicity User interface Viral Load |
| title | In vivo mitochondrial function in HIV-infected persons treated with contemporary anti-retroviral therapy: a magnetic resonance spectroscopy study |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T02%3A01%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=In%20vivo%20mitochondrial%20function%20in%20HIV-infected%20persons%20treated%20with%20contemporary%20anti-retroviral%20therapy:%20a%20magnetic%20resonance%20spectroscopy%20study&rft.jtitle=PloS%20one&rft.au=Payne,%20Brendan%20A%20I&rft.date=2014-01-07&rft.volume=9&rft.issue=1&rft.spage=e84678&rft.epage=e84678&rft.pages=e84678-e84678&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0084678&rft_dat=%3Cgale_plos_%3EA478874611%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1475119775&rft_id=info:pmid/24409305&rft_galeid=A478874611&rft_doaj_id=oai_doaj_org_article_067b4aa45a4d408caf8944ada298a6aa&rfr_iscdi=true |