HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy

Dupin, Nicolas; Buffet, M.; Marcelin, Anne–Geneviève; Lamotte, C.; Gorin, Isabelle; Ait-Arkoub, Zaïna; Tréluyer, Jean‐Marc; Bui, Patrick; Cálvez, Vincent; Peytavin, Gilles

doi:10.1097/00002030-200212060-00006

Cited by 47 publications

(38 citation statements)

References 10 publications

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“…NNRTIs represent a promising approach to combine antiviral efficiency and limited adverse effects. However, recent papers have reported that efavirenz could accumulate in adipose tissue (24) and inhibit triacylglycerol accumulation in mouse preadipose clonal lines (25). We show in this paper that, despite a high extracellular concentration of nevirapine, the intracellular accumulation of this NNRTI was low compared with PIs.…”

Section: Effect Of Pis On Human Adipocytesmentioning

confidence: 47%

Human Immunodeficiency Virus Protease Inhibitors Accumulate into Cultured Human Adipocytes and Alter Expression of Adipocytokines

Vernochet

Azoulay

Duval

et al. 2005

Journal of Biological Chemistry

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Lipodystrophic syndrome is a major side effect of highly active antiviral therapy. Fat tissue redistribution is associated with changes in adipocyte gene expression and in circulating levels of adipocytokines involved in the development of insulin resistance. However, the evidence that HIV drugs accumulate into human adipocytes and have a direct effect on the expression of adipocyte-specific genes is still lacking. To address these questions, we used adipocytes derived from adult stem (hMADS) cells isolated from human adipose tissue. We showed by ELISA that two inhibitors of the HIV protease, lopinavir and ritonavir, accumulated at similar levels during the development of hMADS cells in adipocytes, whereas a non-nucleoside reverse transcriptase inhibitor, the nevirapine, accumulated at lower levels. Two fluorescent protease inhibitors then have been generated to investigate their subcellular localization. The data showed that HIV drugs accumulated into adipocytes and displayed various effects on hMADS cell-derived adipocytes. Indinavir, amprenavir, and nevirapine did not alter differentiation of precursor cells. In contrast, lopinavir, saquinavir, and ritonavir inhibited the development of preadipocytes into adipocytes. In adipocytes, amprenavir increased leptin expression and ritonavir was able to up-regulate tumor necrosis factor-␣, interleukin 6, and leptin expression and downregulate the expression of peroxisome proliferatoractivated receptor ␥ and adiponectin. Intracellular accumulation and localization of HIV drugs into human adipocytes strongly suggest that adipose tissues store these drugs. Because ritonavir can alter the expression of insulin resistance-related cytokines in human adipocytes in a way parallel to the situation observed in vivo upon treatment of HIV-infected patients, we propose that protease inhibitors participate in insulin resistance through a direct effect on adipocytes.Highly active antiretroviral therapy (HAART) 1 combines treatment with three classes of anti-HIV drugs: 1) protease inhibitors (PIs); nucleoside reverse transcriptase inhibitors (NRTIs); and non-nucleoside reverse transcriptase inhibitors (NNRTIs). These drugs have demonstrated their efficiency in improving the lifespan of HIV-infected patients. However, patients under HAART develop metabolic alterations including fat tissue redistribution with peripheral lipoatrophy and increased central adiposity. The lipodystrophic syndrome affects up to 60% treated HIV-infected patients and is emerging as a significant medical concern (1). The adipose tissue of lipodystrophic HIV-infected patients contains clusters of small adipocytes (2) that can result from a defect in differentiation of adipocyte precursors or from metabolic alterations of mature adipocytes. PIs and NNRTIs were detected in adipose tissue of patients, but evidence that HIV drugs accumulate and have a direct effect on the development of human adipocytes are still lacking. It has been recently shown that PIs can enter and accumulate in cultured mouse adipocytes (3, ...

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Section: Effect Of Pis On Human Adipocytesmentioning

confidence: 47%

Human Immunodeficiency Virus Protease Inhibitors Accumulate into Cultured Human Adipocytes and Alter Expression of Adipocytokines

Vernochet

Azoulay

Duval

et al. 2005

Journal of Biological Chemistry

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show abstract

“…Moreover, it should be noted that rilpivirine in cell culture studies is added to serumfree adipocyte culture medium; thus, dose for dose, the effective concentration of rilpivirine in cell culture may be higher than the actual free rilpivirine concentration in blood, where serum proteins may bind substantial amounts of drug (15). In contrast with other NNRTIs, including efavirenz, where information on differential tissue distribution in patients is available (8), there is no data relating to the potential accumulation of rilpivirine at higher concentrations in adipose tissue than in blood.…”

Section: Discussionmentioning

confidence: 99%

Effects of Rilpivirine on Human Adipocyte Differentiation, Gene Expression, and Release of Adipokines and Cytokines

Díaz-Delfín

Domingo

Mateo

et al. 2012

Antimicrob Agents Chemother

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“…68 However, the results of further studies led to a questioning of this possibility. 69,70 More recently, it has been reported that human adipocytes in primary culture are susceptible to HIV-1 infection, and exposure to high levels of TNFa, as occurs in adipose tissue of HALS patients, leads to effective HIV-1 replication and production by adipocytes. 71 On the other hand, cellular components other than adipocytes that are present inside adipose tissue depots may also be the targets of HIV-1 infection.…”

Section: Lipomatosis In Hals Reveals a Potential For Brown Adipocyte mentioning

confidence: 99%

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

2007

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HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy

Cited by 47 publications

References 10 publications

Human Immunodeficiency Virus Protease Inhibitors Accumulate into Cultured Human Adipocytes and Alter Expression of Adipocytokines

Human Immunodeficiency Virus Protease Inhibitors Accumulate into Cultured Human Adipocytes and Alter Expression of Adipocytokines

Effects of Rilpivirine on Human Adipocyte Differentiation, Gene Expression, and Release of Adipokines and Cytokines

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

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