4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 22-25 September 2002, San Diego, CA, USA

SITE-SPECIFIC DIFFERENCES IN THE ACTION OF NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR DRUGS ON ADIPOSE TISSUE INCUBATED IN VITRO WITH ACTIVATED LYMPHOID CELLS AND ITS IMPLICATIONS FOR THE LOCAL INTERACTIONS HYPOTHESIS FOR THE HIV-RELATED ADIPOSE TISSUE REDISTRIBUTION SYNDROME

Antiviral Therapy 2002; 7:L22 (abstract 31)

CM Pond, CA Mattacks, D Sadler and JD Priddle
Department of Biological Sciences, The Open University, Milton Keynes, UK

BACKGROUND: Existing theories of the origin of HIV-related adipose tissue redistribution syndrome cannot adequately explain simultaneous hypertrophy of certain depots and atrophy of others, or its occasional occurrence in untreated HIV-infection. Only site-specific properties of adipose tissue can account for this phenomenon. Perinodal adipocytes have been shown to interact locally with lymphoid cells and these paracrine relationships may be disrupted by nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), or combinations of these drugs.

OBJECTIVES: These experiments explore the hypothesis that hypertrophy of lymphoid tissue-containing depots (the mesentery, omentum, female breast, cervical hump) arises from the disruption of local interactions between perinodal adipocytes and activated lymphoid cells by antiretroviral drugs, which do not occur in depots with few or no lymphoid structures (for example, buttock, thigh, abdominal and other superficial adipose tissue).

METHODS: It is impossible to obtain sufficient biopsy material to test this hypothesis on human tissues, so homologous tissues from eight mature male Dunkin Hartley guinea-pigs fed ad lib on normal chow were studied. Chronic inflammation was induced by repeated injection of lipopolysaccharide near the popliteal lymph nodes. Explants of perinodal and other adipose tissue from popliteal, mesenteric and omental depots, and from the nodeless perirenal and epididymal depots, were incubated with mitogen-activated lymphoid cells in vitro for 2 days with zidovudine, didanosine, lamivudine, stavudine and zidovudine+lamivudine, stavudine+lamivudine and stavudine+didanosine at physiological concentrations (0.1-1 µg/ml). After incubation, basal and maximum (with 10^-5 M norepinephrine) lipolysis were measured from adipocytes prepared from each explant.

RESULTS: All NRTIs, and the combinations thereof, significantly increased lipolysis in all perinodal adipocytes compared to controls incubated without drugs. Samples from the mesentery and omentum were the most responsive, and didanosine was the most consistently lipolytic drug. The effects of all drugs on lipolysis from adipocytes from non-perinodal sites and from the large nodeless depots were minimal.

CONCLUSIONS: At the low concentrations tested, NRTIs modulate the paracrine interactions between perinodal adipocytes and activated lymphoid cells. Stimulation of lipolysis raises extracellular fatty acids and promotes the maturation of additional adipocytes, leading to hypertrophy. These effects account for the clinical finding that hypertrophy of adipose tissue reverses very little during intermissions of antiretroviral drug therapy.

Supported by a research grant to CMP from Bristol-Myers Squibb (USA) under its Lipodystrophy Basic Science Research Program. We also thank GlaxoWellcome for zidovudine and lamivudine for research purposes.

Presenting author: JD Priddle

2002-09-22
31

Copyright © 2002 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.