[O-13] Macrophage recruitment in adipose tissue from HIV-infected patients under ART: concomitant presence of classically activated pro-inflammatory M1 and alternatively activated M2 macrophages

9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV

19-21 July 2007, Sydney, Australia

MACROPHAGE RECRUITMENT IN ADIPOSE TISSUE FROM HIV-INFECTED PATIENTS UNDER ART: CONCOMITANT PRESENCE OF CLASSICALLY ACTIVATED PRO-INFLAMMATORY M1 AND ALTERNATIVELY ACTIVATED M2 MACROPHAGES

ANTIVIRAL THERAPY 2007; 12(Suppl. 2):L13 (abstract no. O-13)

V Avettand-Fenoel¹, M Kim², B Antuna², A Borjabad¹, U Hazan¹, E Lanoy³, D Costagliola³, P Leclercq⁴, JP Bastard² and J Capeau²
¹Faculty of Medicine Cochin Université Paris-5, Paris, France; ²Inserm U680, Université Paris-6, AP-HP Hopital Tenon, Paris, France; ³Inserm U720, Université Paris-6, Paris, France; ⁴CHU Grenoble, Grenoble, France

OBJECTIVES: Invading macrophages are present in lipoatrophic patients’ adipose tissue. Macrophage activation can lead to two separate states: M1, or classically activated macrophages, with enhanced pro-inflammatory cytokine production; and M2, or alternatively activated macrophages, generating high levels of anti-inflammatory cytokines. We evaluated 1) the phenotype of the macrophages present in lipoatrophic adipose tissue and 2) the evolution of this phenotype in fat tissue from patients stopping any ART for 6 months.

METHODS: Affymetrix microarray assays were performed in abdominal subcutaneous fat samples from six non- obese controls and five HIV-infected patients under PI and stavudine. Expression of genes specific for adipocytes, M1 and M2 macrophages was compared. The results were validated by quantitative RT-PCR (QRT-PCR) in, respectively, 12 and 7 other controls and patients. The expression of some M1 and M2 macrophage-specific markers was also evaluated by QRT-PCR in 20 paired biopsies from HIV-infected patients obtained before stopping ART and 6 months after.

RESULTS: Affymetrix microarray analysis indicates that expression of the reference gene TBP was equivalent in controls and patients while that of the adipocyte marker perilipin decreased twofold, in agreement with the strong decrease in the adipocyte proportion in patients’ fat tissue. A strong increase in M1 marker expression was observed in patients’ samples as compared with controls: CD68 (×4.9), CD14 (×9.4), CCL2 (×3.4). Similarly, a strong increase in the expression of M2 markers was present: CD163 (×2.9), chitinase (×89.3) and CH3L1 (×28.2). The microarray results were verified by QRT-PCR for CD14 and chitinase and confirmed the highly significant increase of M1 and M2 markers in patients’ fat. We then evaluated whether a 6-month ART-interruption modified the expression of M1 and M2 markers. CD68 expression was decreased in patients stopping stavudine or zidovudine and expression of CD14 decreased in patients stopping PI; expression of the M2 markers CD163 and chitinase remained unmodified.

CONCLUSION: In HIV-infected patients under ART, pro- inflammatory M1 and anti-inflammatory M2 macrophages are concomitantly present in lipodystrophic adipose tissue. Stopping ART allows a specific reduction in pro-inflammatory macrophages.

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2007-07-24
O-13

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