Genetic and functional mitochondrial assessment of HIV-infected patients developing HAART-related hyperlactatemia.
BACKGROUND
Mitochondrial damage of HIV and antiretrovirals, especially nucleoside-analogue interference on mitochondrial DNA (mtDNA) replication, is reported to underlay highly active antiretroviral therapy (HAART)-related hyperlactatemia, but scarce approaches have been performed to correlate clinical manifestations and mitochondrial abnormalities.


METHODS
We obtained lymphocytes and monocytes of 26 HIV-infected and treated patients who developed hyperlactatemia and after recovery, 28 nonhyperlactatemic HIV subjects on HAART, 31 naive individuals, and 20 uninfected controls. Mitochondrial replication and transcription analysis were performed by quantitative real-time PCR, mitochondrial translation quantification by western blot and mitochondrial enzymatic activities by spectrophotometry.


RESULTS
Mitochondrial parameters decreased during hyperlactatemia and improved at recovery. Mitochondrial replication and transcription species were reduced (P = 0.16 and P = 0.71), but the most significant decay was observed on mitochondrial protein content (P < 0.05) and mitochondrial complexes III and IV activities (P < 0.01 and P < 0.001). During hyperlactatemia lactate level correlated complexes III and IV function (P < 0.05). After recovery mitochondrial parameters achieved values of nonhyperlactatemic HIV individuals, which were lower than ranges of naive subjects and uninfected controls.


CONCLUSIONS
HIV and HAART-related hyperlactatemia is associated with a general mitochondrial impairment which reverts after recovery. Mitochondrial biochemistry show a better correlation with lactate levels than mitochondrial genetics suggesting that mitochondrial function could be a better marker of hyperlactatemia development than mtDNA content.
Mitochondrial Research Laboratory, Internal Medicine Department, Hospital Clínic of Barcelona, IDIBAPS, University of Barcelona and CIBER de Enfermedades Raras, CIBERER, Barcelona, Spain.
Glòria
G
Garrabou
Constanza
C
Morén
Jose Miguel
JM
Gallego-Escuredo
Ana
A
Milinkovic
Francesc
F
Villarroya
Eugenia
E
Negredo
Marta
M
Giralt
Francesc
F
Vidal
Enric
E
Pedrol
Esteban
E
Martínez
Francesc
F
Cardellach
Josep Maria
JM
Gatell
Oscar
O
Miró
D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007773:Lactates / Q000097:blood*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000378:metabolism; D000077278:RNA, Mitochondrial
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D007773:Lactates; D024101:Mitochondrial Proteins; D000077278:RNA, Mitochondrial; D012313:RNA