AEGiS-15IAC: Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine and zidovudine containing regimens.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine and zidovudine containing regimens.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WePeB5948)

Jones SP, Qazi N, Walker UA, Moyle G, Back DJ, Pirmohamed M
University Of Liverpool, Liverpool, United Kingdom

BACKGROUND: Lipoatrophy (LA) in HIV patients has been attributed to the inhibition of mitochondrial DNA by the nucleoside reverse transcriptase inhibitors (NRTIs), while protease inhibitors (PIs) are thought to be responsible for fat accumulation and the metabolic changes. PIs, but not NRTIs, have also been shown to modulate the secretion of adipokines such as adiponectin. In order to further understand the relationship between mitochondrial toxicity, adipokine expression and LA, we have undertaken a cross-sectional analysis of patients on d4T and AZT -based regimens with LA in comparison to drug-naïve individuals.

METHODS: Cross sectional study of subcutaneous fat, plasma and peripheral blood mononuclear cells (PBMCs) from HIV+ patients with LA on first line antiretroviral therapy with AZT (n=6) or d4T (n=12) and compared to 18 PI naïve HIV+ untreated and HIV- controls. The samples were assessed for mitochondrial DNA depletion (mtDNA), and protein and mRNA levels of adiponectin, TNF-ialpha, IL-6 and SREBP1a/c.

RESULTS: In patients with LA treated with d4t, but not AZT, the respiratory subunit COXII/COXIV-ratio was reduced in both adipose tissue (57.2± 7.7 vs 131.3± 23, p<0.01) and in isolated PBMCs (75.1± 4 vs 91.2± 4.6, p<0.05). There was a non-significant decrease in mtDNA in both adipose tissue and PBMCs in patients with LA. Tissue adiponectin mRNA levels (0.6± 0.1 vs 1.1± 0.1, p<0.01) and the transcription factors SREBP1a (-1.1± 0.1 vs -0.8± 0.1, p<0.05) and 1c (0.7± 0.1 vs 1.0± 0.1, p<0.05) were lower in the d4T LA patients than in controls. IL6 mRNA and protein levels were up regulated, although this was non-significant, while TNF-ialpha mRNA showed no difference. Analysis of plasma showed that adiponectin levels were reduced by 40% in patients on d4T and 50% on AZT.

CONCLUSIONS: Our data show that patients with LA on d4T-based regimens show evidence of mitochondrial toxicity. Adiponectin and SREBP isoforms are reduced in both AZT and d4T treated patients with LA in the absence of PI exposure. Inflammatory cytokines were not up regulated in LA.

Keywords: AEGIS, Stavudine, Zidovudine, HIV, Tumor Necrosis Factors, Acquired Immunodeficiency Syndrome, HIV Seropositivity, Anti-HIV Agents, HIV Infections, HIV-Associated Lipodystrophy Syndrome, DNA, Mitochondrial, Adipose Tissue, HIV-1, HIV Protease Inhibitors, Cross-Sectional Studies, Humans, methods

040711
WePeB5948