title: Mitochondrial damage associated with long-term antiretroviral treatment: associated alteration or causal disorder?
abstract: Combination of antiretroviral drugs has dramatically improved the prognosis of human HIV infection but is also associated with many adverse effects, the mitochondrial origin of which is discussed. In this study using extensive diagnostic procedures set up for inherited mitochondrial disorders, we analyzed HIV patients under active antiretroviral therapy who complained of severe adverse symptoms unexplained by HIV. All these patients had been treated for at least 5 years. They all had significant mitochondrial damage as evidenced by the diverse combination of lactate accumulation in blood or cerebrospinal fluid, mitochondrial morphologic alterations in muscle, and biochemical defects in muscle and liver, which designated mitochondrial DNA (mtDNA) as the main target of the toxic mechanisms. Southern blot and/or polymerase chain reaction -based analyses disclosed multiple deletions of the muscle mtDNA and reduction of the muscle and/or liver mtDNA copy number in a majority of the patients. In opposition to muscle and liver, blood mononuclear cells were devoid of significant biochemical or genetic alterations. Whether the mitochondrial toxicity is directly responsible for the patients' adverse symptoms remains disputable, because the investigations were transversal. Its severity argues for its clinical relevance, however. The skewed tissue distribution of mitochondrial alterations indicates potential pitfalls in the needed future prospective studies.
authors.affiliation: Unité des maladies infectieuses, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vittecoq
authors.forename: Claude
authors.initials: C
authors.lastname: Jardel
authors.forename: Cyrille
authors.initials: C
authors.lastname: Barthélémy
authors.forename: Lélia
authors.initials: L
authors.lastname: Escaut
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cheminot
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chapin
authors.forename: Damien
authors.initials: D
authors.lastname: Sternberg
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.forename: Anne
authors.initials: A
authors.lastname: Lombès
mesh_terms: D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000097:blood / Q000187:drug effects / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D019344:Lactic Acid