Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy.
The nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine, may deplete mitochondrial (mt) DNA in human tissues by inhibiting the mitochondrial polymerase gamma, a setting, which is associated with hyperlactatemia. The aim of the present study was to examine whether hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV-infected patients (35 patients on HAART including at least one NRTI (HIV-NRTI) and 7 patients never treated with antiretroviral drugs (NAIVE)) and 14 healthy controls. Whole body oxidative capacity (DeltaGOX) was estimated in HIV-infected patients by indirect calorimetry. Hyperlactatemia (>or=2.0 mM) was detected in six HIV-NRTI, who all used Stavudine (P < 0.01), displayed depleted sm-mtDNA (P < 0.02) and decreased DeltaGOX (P < 0.01) compared with normolactatemic HIV-NRTI (n = 29). NAIVE displayed decreased sm-mtDNA (P < 0.05), increased HIV-RNA (P < 0.01) and increased plasma TNF-alpha (P < 0.05) compared to all HIV-NRTI (n = 35), in turn displaying decreased sm-mtDNA (P < 0.01) compared to healthy controls. Thus, hyperlactatemia in HIV-NRTI may be associated with pronounced depletion of sm-mtDNA, decreased oxidative capacity and current stavudine therapy. Further, HIV may deplete sm-mtDNA of NAIVE, which in part could be mediated through an enhanced pro-inflammatory response.
Haugaard
Steen B
SB
Department of Infectious Diseases, Hvidovre University Hospital, Copenhagen, Denmark. sbhau@dadlnet.dk
Andersen
Ove
O
Pedersen
Steen B
SB
Dela
Flemming
F
Richelsen
Bjørn
B
Nielsen
Jens Ole
JO
Madsbad
Sten
S
Iversen
Johan
J
D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D004272:DNA, Mitochondrial / Q000097:blood / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D019344:Lactic Acid