8th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV San Francisco, California - September 24 - 26, 2006

INHIBITION OF RESISTIN DEGRADATION BY AN HIV PROTEASE INHIBITOR: A MECHANISM FOR METABOLIC ABNORMALITIES CAUSED BY HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

Antiviral Therapy 2006; 11:L30 (abstract no. 45)

WJ Geese, O Flint, R Parker, M Noor and K Ranade
Pharmaceutical Research Institute Bristol-Myers Squibb Company Princeton, NJ, USA

BACKGROUND: The mechanistic basis of metabolic abnormalities and body composition changes caused by Highly Active Anti-Retroviral Therapy (HAART) is poorly understood. Elsewhere (Ranade et al. abstract), we described a cluster of individuals in the ACTG5005s trial who had a normal metabolic profile prior to therapy but developed hypertriglyceridemia, hypercholesterolemia, insulin resistance, lipoatrophy and increased trunk-to-limb fat ratios after exposure to HAART. Previously, using a candidate gene approach, we found highly significant association between this cluster and single nucleotide polymorphisms in resistin, a gene previously implicated in obesity and insulin resistance. We hypothesized that HIV protease inhibitors, by interfering with the degradation of resistin by endogenous proteases, could increase resistin levels which, in turn, may contribute to metabolic abnormalities in genetically susceptible individuals on HAART.

METHODS: We evaluated three endogenous aspartyl proteases, renin, cathepsins D and E for their ability to cleave resistin in vitro. For comparison, we also evaluated HIV protease, another aspartyl protease and trypsin, an unrelated protease which has broad substrate specificity and is known to degrade numerous proteins. Interactions with HIV protease inhibitors were also evaluated.

RESULTS: Both cathepsins and HIV protease specifically cleaved resistin in vitro to generate a ca. 7 kDa fragment. In contrast, the highly specific protease renin did not cleave resistin whereas trypsin completely degraded it. Resistin cleavage by cathepsins D and E was inhibited by micromolar concentrations of ritonavir, an HIV protease inhibitor (PI) known to cause metabolic abnormalities. In contrast, atazanavir, an HIV protease inhibitor with reduced ability to cause metabolic abnormalities failed to inhibit resistin cleavage by cathepsins at concentrations up to 100 micromolar. Consistent with expectation, micromolar concentrations of both PIs prevented cleavage by HIV protease and neither PI inhibited resistin degradation by trypsin.

CONCLUSIONS: Taken together, these results provide a biochemical rationale for the genetic association between resistin and metabolic abnormalities caused by HAART, and provide new insight into resistin physiology. Furthermore, an assay of resistin cleavage could be developed to screen for anti-retrovirals that do not inhibit endogenous proteases that degrade resistin, and are thus less likely to perturb resistin levels.

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2006-09-24
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