10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

GENOME-WIDE TRANSCRIPTOMIC ANALYSIS REVEALS DISTINCT PATTERNS OF ALTERED GENE EXPRESSION IN SUBCUTANEOUS ADIPOSE TISSUE ASSOCIATED WITH HIV-1 INFECTION, ANTIRETROVIRAL TREATMENT AND LIPODYSTROPHY

Antiviral Therapy 2008; 13(Suppl. 4):A25 (abstract no. P-05)

P Domingo¹, JP Guallar², JM Gallego-Escuredo², J Díaz-Delfín², JC Domingo², M Alegre¹, MM Gutierrez¹, MG Mateo¹, M Giralt² and F Villarroya^2
1Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; ²University of Barcelona, Barcelona, Spain

AIM: The relative contribution of the distinct pathogenic events leading to lipoatrophy in HIV type-1 (HIV-1)infected, antiretroviral-treated patients is poorly known. To ascertain the major molecular events associated with the appearance of lipoatrophy, we performed whole-genome transcriptomic analysis of subcutaneous fat from distinct sets of patients in comparison with healthy controls.

METHODS: We obtained RNA from subcutaneous adipose tissue biopsies from four groups of individuals: HIV- 1-uninfected healthy controls, HIV-1-infected patients naïve to antiretroviral treatment and HIV-1-infected patients under treatment without or with lipodystrophy, including peripheral lipoatrophy. Microarray analysis was performed using eight distinct individual RNA samples for every group and chemoluminiscence-based Applied Biosystems Human-Genome Survey arrays. Differential gene expression in relation to biological processes was analysed using the PANTHER onthology tool. Validation of results was performed by quantitative TaqMan reverse transcriptase-PCR of selected transcripts representative of functional categories of genes.

RESULTS: Adipose tissue from untreated HIV-1-infected patients had altered expression of genes of ‘inflammation mediated by chemokines and cytokines’, ‘complementmediated immunity’ and ‘interferon-mediated immunity’ as well as of ‘T-cell activation’. Several of these alterations remained in treated patients with and without lipodystrophy. Macrophage-mediated immunity was altered in treated patients only, and more deeply in those with lipodystrophy. MHC-I-mediated immunity and MHC-II-mediated immunity were altered only in patients with lipodystrophy. Lipid metabolism and tricarboxylic acid cycle-related gene expression were also modified in fat from all the HIV-1-infected patient groups, although alterations were more profound in treated patients and in those with lipodystrophy. Mitochondrial oxidative phosphorylation and electron transfer-related gene expression were altered only in adipose tissue from treated patients, and more deeply in those showing lipodystrophy. Only adipose tissue from patients with lipodystrophy showed a modification in apoptosis- related gene expression. Another pathway in which gene expression was altered was detoxification-related (only in treated patients).

DISCUSSION: Alterations of gene expression in relation to immunity, inflammation and metabolism appear in adipose tissue from non-treated HIV-1-infected patients. Treated patients, in addition to disturbances in gene expression for those processes, show modifications in gene expression for metabolic pathways related to mitochondrial oxidation, macrophage activation and detoxification. Apoptosis-related gene expression is specifically altered in association with full- blown lipoatrophy. Present results highlight a role for HIV-1 infection in addition to antiretroviral treatment in eliciting adipose tissue alterations. Establishment of direct or indirect actions of HIV-1 on adipose tissue, identification of cellular actors other than macrophages as involved in the proinflammatory response of adipose tissue to HIV-1 infection and knowledge of the molecular basis for the specific alterations in energy metabolism appear as novel directions for research in HIV-1 lipodystrophy in the light of present findings.

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2008-11-06
P-05

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