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Antimicrobial Agents and Chemotherapy, December 2006, p. 3998-4004, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00625-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Long-Term Treatment with Lopinavir-Ritonavir Induces a Reduction in Peripheral Adipose Depots in Mice

INSERM, U568, Nice, F-06107, France,¹ Université de Nice Sophia-Antipolis, Faculté de Médecine, av de Valombrose, Nice, F-06107, France,² CHU de Nice, Service d'Infectiologie Hôpital l'Archet-1, route de saint Antoine de Ginestière, 06202 Nice, France,³ CHU de Nice, Laboratoire Central d'Anatomie Pathologique, Hôpital Pasteur, 20 av de la voie romaine, BP 69, 06002 Nice, France,⁴ CHU de Nice, Laboratoire de Pharmacologie-Toxicologie, Hôpital Pasteur, 20 av de la voie romaine, BP 69, 06002 Nice, France,⁵ INSERM, U626, Marseille, F-13385, France,⁶ Université de la Méditerranée, Faculté de Médecine La Timone, 26 bd J Moulin, 13385 Marseille, France⁷

Received 22 May 2006/ Returned for modification 6 July 2006/ Accepted 14 September 2006

Highly active antiretroviral therapy (HAART) of human immunodeficiency virus-infected patients is associated with adverse effects, such as lipodystrophy and hyperlipidemia. The lipodystrophic syndrome is characterized by a peripheral lipoatrophy and/or fat accumulation in the abdomen and neck. In order to get insights into the physiopathological mechanisms underlying this syndrome, we treated mice with protease inhibitors (PIs) over a long period of time. Although atazanavir-treated mice presented the same circulating triglyceride concentration as control mice, lopinavir-ritonavir-treated mice rapidly became hypertriglyceridemic, with triglyceride levels of 200 mg/dl, whereas control and atazanavir-treated animals had triglyceride levels of 80 mg/dl. These results obtained with mice reproduce the metabolic disorder observed in humans. White adipose tissue (WAT) was analyzed after 8 weeks of treatment. Compared to the control or atazanavir treatment, lopinavir-ritonavir treatment induced a significant 25% weight reduction in the peripheral inguinal WAT depot. By contrast, the profound epididymal WAT depot was not affected. This effect was associated with a 5.5-fold increase in SREBP-1c gene expression only in the inguinal depot. Our results demonstrate that the long-term treatment of mice with PIs constitutes an interesting experimental model with which some aspects of the lipoatrophy induced by HAART in humans may be studied.

Published ahead of print on 25 September 2006.