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Whole genome transcriptomic analysis of adipose tissue from patients at distinct stages of progression of HIV-1/HAART-associated lipodystrophy reveals alterations in inflammation and metabolism due to HIV-1 infection before antiretroviral treatment
Presented by Francesc Villarroya, Spain.
F. Villarroya1, J.P. Guallar1, P. Domingo2, J.C. Domingo1, M. Alegre3, M. Giralt1
1University of Barcelona. Institut de Biomedicina (IBUB), Biochemistry and Molecular Biology, Barcelona, Spain, 2Hospital de la Santa Creu i Sant Pau, Internal Medicine, Barcelona, Spain, 3Hospital de la Santa Creu i Sant Pau, Dermatology, Barcelona, Spain
Background: HIV-1/HAART-associated lipodystrophy (HALS) appears in a sub-set of HIV-1-infected patients after anti-retroviral treatment. A complex interaction of HIV-1 infection and treatment-associated events are considered to be responsible for the syndrome.
Methods: To ascertain the major molecular events associated to the appearance of HALS, we performed whole-genome expression analysis of adipose tissue RNA from four groups of patients: HIV-1-uninfected healthy controls, HIV-1-infected patients naive to HAART and HIV-1-infected patients under HAART without or with lipodystrophy. Microarray analysis was performed using 8 distinct individual RNA samples for every group and the chemoluminiscence-based Applied Biosystems Human Genome Survey arrays. Further validation of results by quantitative TaqMan RT-PCR of selected transcripts representative of functional categories of genes was performed.
Results: Adipose tissue from HIV-1-infected patients without HAART showed altered expression of genes of inflammation mediated by chemokines and cytokines, of complement-mediated, interferon-mediated and B-cell antibody-mediated immunity as well as of T-cell activation. These alterations remained in HAART-treated patients with and without HALS. Macrophage-mediated immunity was altered in HAART-treated patients only, and more deeply in HALS patients. MHC-I and MHC-II-mediated immunity was altered only in HALS patients. Carbohydrate and fatty acid metabolism and tricarboxylic acid cycle-related gene expression was also altered in fat from all the HIV-1-infected patient groups, although alteration was more profound in HAART-treated and HALS patients. Oxidative phosphorylation and electron transfer-related gene expression was altered only in fat from patients under HAART and more deeply in those showing HALS. HALS patients were the only that showed altered apoptosis-related gene expression. Other pathways for which gene expression was altered were PDGF-signaling (only in HALS patients) and angiogenesis (in all HIV-1-infected patient groups).
Conclusions: HIV-1 infection, prior to treatment, causes early alterations in adipose tissue gene expression, evidenced by induction of a pro-inflammatory status before full-blown macrophage infiltration, and first signs of impaired adipogenesis and lipid metabolism.