title: Mitochondrial dysfunction in CD4+ lymphocytes from stavudine-treated HIV patients.
abstract: HIV therapy with nucleoside analogue reverse transcriptase inhibitors (NRTI) such as stavudine remains in widespread use in resource-limited nations due to potent efficacy, convenience of formulation and lack of practical alternatives. However, it remains unclear whether adverse side effects with NRTI include reduced mitochondrial respiratory function, particularly in peripheral blood lymphocytes (PBLs). The aim of this study was to determine whether stavudine-based highly active antiretroviral therapy (HAART) is associated with impaired mitochondrial respiratory transport chain function in patient derived CD4+PBLs. CD4+PBLs were isolated from asymptomatic HIV-infected patients treated with stavudine-HAART for 3 months (n=10), HIV-infected patients not on treatment (n=9) and uninfected controls (n=18). The basal mitochondrial oxygen consumption of CD4+PBLs from stavudine-treated patients was reduced relative to that of untreated HIV-infected patients and controls (stavudine treated group, 4.22 (25% 2.16, 75% 8.84); control uninfected, 11.2 (25% 3.95, 75% 16.6); untreated 18.1 (25% 11.8, 75% 37.9)ng oxygen atoms/min/ml). Maximal oxygen consumption (stimulated with the proton ionophore FCCP) in cells from stavudine treated patients was also reduced relative to that of untreated patients and controls (stavudine treated, 24.4+/-10.5; control uninfected, 50.6+/-39.5; untreated, 68.8+/-41.1 ng oxygen atoms/min/ml). Citrate synthase activities, relative mitochondrial volume (by electron microscopy) and mtDNA copy numbers per cell were not different between groups. Therapy with stavudine results in impaired mitochondrial function in CD4+PBLs that does not appear to be due to reduced mitochondrial volume or DNA content and cannot be attributed to infection with HIV.
authors.affiliation: Centre for Virology, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Einsiedel
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Cherry
authors.forename: Freya L
authors.initials: FL
authors.lastname: Sheeran
authors.forename: Anna
authors.initials: A
authors.lastname: Friedhuber
authors.forename: Steve L
authors.initials: SL
authors.lastname: Wesselingh
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pepe
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000032:analysis; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000139:chemically induced*; D010101:Oxygen Consumption; D018119:Stavudine / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D018119:Stavudine; D002950:Citrate (si)-Synthase