Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens.
OBJECTIVE
Despite evidence for the role of adipokines such as adiponectin in the metabolic toxicities of protease inhibitor (PI)-treated patients, little is known about their role in nucleoside reverse transcriptase inhibitor (NRTI)-induced lipoatrophy (LA). We analyzed the relations between mitochondrial toxicity, adipokine expression, and clinical LA in peripheral blood mononuclear cells (PBMCs) and adipose samples from individuals treated with stavudine (d4T) or zidovudine (ZDV) in comparison to patients undergoing highly active antiretroviral therapy (HAART) as well as HIV-negative individuals.


METHODS
In this cross-sectional analysis, we studied 18 PI-naive HIV-infected patients with LA treated with d4T (d4T+LA+ [n = 12]) or zidovudine (ZDV+LA+ [n = 6]) in comparison to HAART-treated patients with (HAART+LA+ [n = 8]) and without (HAART+LA- [n = 8]) LA as well as HIV-negative controls (n = 12). Adipose samples were assessed for protein and/or messenger RNA (mRNA) levels of adiponectin, tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, and sterol regulatory element-binding protein (SREBP) 1a/c in all groups, whereas adipose and PBMC samples from the d4T+LA+, ZDV+LA+, and HIV-negative subgroups were assessed for mitochondrial DNA (mtDNA) depletion and cytochrome c-oxidase (COX) II/COX IV ratios.


RESULTS
There was no change in mtDNA levels in adipose or PBMC samples in NRTI-treated patients with LA, although patients treated with d4T had reduced COX II/COX IV ratios in adipose and PBMC samples. Adipose tissue adiponectin mRNA and plasma levels were reduced in the d4T- and ZDV-treated patients regardless of the use of PIs. Tissue SREBP1c mRNA levels were also significantly reduced in both NRTI groups when compared with the HIV-negative controls. Significant reductions in SREBP1c levels were also evident with the HAART+LA+ group when compared with HAART+LA- controls.


CONCLUSIONS
Patients with LA on d4T-based regimens show evidence of mitochondrial respiratory chain dysfunction, whereas the d4T- and ZDV-based regimens also demonstrated reduced SREBP1c and adiponectin levels, findings that have previously been shown with PIs.
Jones
Simon P
SP
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom.
Qazi
Nadeem
N
Morelese
John
J
Lebrecht
Dirk
D
Sutinen
Jussi
J
Yki-Jărvinen
Hannele
H
Back
David J
DJ
Pirmohamed
Munir
M
Gazzard
Brian G
BG
Walker
Ulrich A
UA
Moyle
Graeme J
GJ
D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active; D004272:DNA, Mitochondrial / Q000097:blood; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D039682:HIV-Associated Lipodystrophy Syndrome / Q000188:drug therapy*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D018119:Stavudine / Q000009:adverse effects*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015215:Zidovudine / Q000009:adverse effects*
D052242:Adiponectin; D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015850:Interleukin-6; D018894:Reverse Transcriptase Inhibitors; D051780:Sterol Regulatory Element Binding Protein 1; D014409:Tumor Necrosis Factor-alpha; D015215:Zidovudine; D018119:Stavudine