500   Hyperlipoproteinemia in HIV Patients Is Linked to Sterol- Regulatory Element-Binding Protein (SREBP)-1c.

A. R. Miserez*^1,2, L. Barella¹, P. Y. Muller¹, M. Schwietert², P. Erb¹, T. Klimkait¹, P. L. Vernazza³, and M. Battegay².
¹Univ. of Basel;²Univ. Clin., Basel; and³Cantonal Hosp., St. Gall, Switzerland.

Background:Antiretroviral protease inhibitor (PI) therapy is often associated with hyperlipoproteinemia.

Methods:To uncover the molecular basis, candidate genes were investigated. In vitro , the influence of PIs on the activity of specific genes was determined using dual luciferase reporter gene assays. In vivo , novel polymorphic gene markers were associated with the development of hyperlipoproteinemia.

Results:Sequence homologies between the HIV-1 and the site-1 protease (S1P), the latter activating the SREBP- 1c and SREBP-2 pathways, were discovered. In vitro , addition of PIs to the medium inhibited the activity of the S1P/SREBP-1c-dependent fatty acid synthase reporter gene (-44%, P < 0.0001), but not the activity of the S1P/ SREBP-2-dependent low-density lipoprotein receptor reporter gene. In vivo , a novel polymorphism (3´322C>G: allele "2") discovered in the SREBP-1c gene and polymorphic markers in the SREBP-2 and apolipoprotein E genes were investigated in control (N = 2727) and HIV-1-infected (N = 67) subjects. In PI-treated, homozygous SREBP-1c 3´322C>G carriers (genotype 22), plasma total cholesterol (TC) remained unchanged, whereas in 3´322C>C carriers (genotypes 11/12), TC increased. The increases in TC were different between genotype groups (P = 0.0314). As expected from these results, genotype 11/12 carriers had more frequent TC increases following PIs than genotype 22 carriers (P = 0.0096). The increases in plasma TC were significantly correlated with increases in insulin and leptin (P = 0.0049, P = 0.0004). Surprisingly, these correlations were present in genotype 11/12 carriers only.

Conclusions:Genotype 22 carriers had a lower risk of being affected by PI-associated hyperlipoproteinemia than genotype 11/12 carriers. Differences in the mRNA stabilities (3´322C>C/3´322C>G) may explain our findings since there is evidence from others that SREBP-1c is regulated at the mRNA level. Thus, we report the first polymorphism of pharmacogenetic relevance in a gene encoding a key regulator of cholesterol, triglyceride, and glucose metabolism. Testing prior to antiretroviral treatment may predict PI-associated hyperlipoproteinemia.