Lipodystrophy is an adverse affect of highly active anti-retroviral therapy (HAART) regimens used in patients with HIV disease. The syndrome is thought to be genetically determined, but unlike the rare lipodystrophy syndromes in patients without HIV, predisposition is thought to be polygenic. Interleukin 6 has been implicated in the pathogenesis of the syndrome. Two IL-6 gene polymorphisms, G-₅₉₇A and G-₁₇₄C, are in linkage disequilibrium, and are thought to be functionally active [1]. IL-6 also drives the expression of the LDL-R, which is important in the pathogenesis of hyperlipidaemia, a hallmark of lipodystrophy [2]. In order to investigate further the interaction between HAART and the IL-6 genotype, we have investigated whether HIV protease inhibitors can modulate LDL-R expression and IL-6 secretion and whether this is affected by the IL6 genotype.

Healthy individuals were genotyped for the G-₅₉₇A and G-₁₇₄C SNPs in the IL-6 gene by real-time PCR, and haplotypes determined. Blood samples were drawn from five individuals with the GG/GG and four individuals with the AA/CC haplotypes. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured for 24 h with saquinavir alone, saquinavir with ritonavir, atazanavir alone, atazanavir with ritonavir and ritonavir alone. IL-6 concentrations were analyzed by ELISA and the LDL-R expression was analyzed by flow cytometry. Statistical analysis was performed by anova for data that were normally distributed, and Mann-Whitney U test for other data.

The frequency of both haplotypes was similar to that previously reported in the literature and obeyed Hardy-Weinberg equilibrium. The IL-6 concentration in individuals with the GG/GG genotype was higher than in the AA/CC individuals after stimulation by LPS, although this just failed to reach significance ( p = 0.07). Saquinavir with ritonavir and ritonavir alone caused an increase in IL-6 concentrations in a dose-dependent manner, with statistical significance being attained at 20 µm ( p < 0.05) for both drugs together and at 10 µm ( p < 0.005) for ritonavir alone. Saquinavir alone, saquinavir and ritonavir and ritonavir alone increased LDL-R expression on lymphocytes in a dose-dependent manner ( p < 0.05). Atazanavir alone did not increase LDL-R expression, although there was a trend towards an increase in IL-6 concentrations ( p = 0.06). There was no significant relationship between the IL-6 haplotypes and HIV protease inhibitor stimulated LDL-R expression and IL-6 concentrations.

Saquinavir and ritonavir, which have been implicated in the pathogenesis of lipodystrophy, increase IL-6 and LDL-R expression. By contrast atazanavir, which is thought to be free of metabolic adverse effects, had little effect on LDL-R expression. These changes seemed to be independent of IL-6 haplotypes, although our study is limited by the small numbers studied.

1. Fishman D, et al .J Clin Invest 1998; 102:1369.
2. Gierens H,et al. Arterioscler Thromb Vasc Biol 2000; 20: 1777.