Ageing, metabolism and HIV

International audiencen.

Antiretroviral-Related Adipocyte Dysfunction and Lipodystrophy in HIV-Infected Patients: Alteration of the PPARγ-Dependent Pathways

Lipodystrophy and metabolic alterations are major complications of antiretroviral therapy in HIV-infected patients. In vitro studies using cultured murine and human adipocytes revealed that some protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were implicated to a different extent in adipose cell dysfunction and that a chronic incubation with some PIs decreased mRNA and protein expression of PPARγ. Defective lamin A maturation linked to PI inhibitory activity could impede the nuclear translocation of SREBP1c, therefore, reducing PPARγ expression. Adipose cell function was partially restored by the PPARγ agonists, thiazolidinediones. Adverse effects of PIs and NRTIs have also been reported in macrophages, a cell type that coexists with, and modulates, adipocyte function in fat tissue. In HIV-infected patients under ART, a decreased expression of PPARγ and of PPARγ-related genes was observed in adipose tissue, these anomalies being more severe in patients with ART-induced lipoatrophy. Altered PPARγ expression was reversed in patients stopping PIs. Treatment of patients with agonists of PPARγ could improve, at least partially, the subcutaneous lipoatrophy. These data indicate that decreased PPARγ expression and PPARγ-related function, resulting from ART-induced adipose tissue toxicity, play a central role in HIV-related lipoatrophy and metabolic consequences

PPAR and Liver Injury in HIV-Infected Patients

Due to the introduction of active HIV antiretroviral treatment, AIDS-related morbidity and mortality have markedly decreased and liver diseases are now a major cause of morbidity and mortality in HIV-infected patients. Chronic liver injury encompasses a wide spectrum of diseases due to HCV and HBV coinfection, drug-related toxicity, and NASH. HIV-infected patients who are receiving treatment present with a high prevalence of metabolic complications and lipodystrophy. Those patients are at high risk of nonalcoholic fatty liver disease, the liver feature of the metabolic syndrome. This review will focus on (1) the liver injuries in HIV-infected patients; (2) both the current experimental and human data regarding PPAR and liver diseases; (3) the interactions between HIV and PPAR; (4) the potential use of PPAR agonists for the management of HIV-related liver diseases

Les lipodystrophies secondaires aux traitements antirétroviraux de l’infection par le VIH

Les traitements antirétroviraux de l’infection par le VIH sont responsables d’effets secondaires parfois sévères qui touchent en priorité le tissu adipeux, modifiant sa localisation (lipodystrophie avec lipoatrophie périphérique et hypertrophie centrale) et les paramètres du métabolisme glucido-lipidique (dyslipidémie, diabète). Les deux principales classes thérapeutiques, inhibiteurs de protéase et analogues nucléosidiques, sont délétères sur ces paramètres par des mécanismes différents mais qui convergent sur le tissu adipeux. Certaines des molécules de ces deux classes modifient profondément sa différenciation, son métabolisme, sa fonction mitochondriale et l’équilibre des hormones (leptine, adiponectine) et cytokines (TNFα, IL-6) qu’il sécrète. Ce syndrome de lipodystrophie induit un risque cardiovasculaire et de stéatohépatite grevant le pronostic vital. Le traitement reste difficile chez les patients atteints et privilégie le remplacement des molécules les plus délétères par des molécules antirétrovirales plus récentes et moins agressives sur le tissu adipeux.HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFα, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue

HIV-associated lipodystrophy: from fat injury to premature aging

Combination antiretroviral therapy (cART) against HIV infection dramatically reduces AIDS-related morbidity. However, many patients under cART display HIV-associated lipodystrophy. Moreover, some develop early agerelated comorbidities. Thymidine analog reverse transcriptase inhibitors (tRNTIs) are mainly responsible for peripheral lipoatrophy, and protease inhibitors (PIs) for fat hypertrophy and metabolic complications. Longterm HIV infection probably also causes fat alterations. Severe mitochondrial toxicity and oxidative stress cause lipoatrophy, whereas the hypertrophy of upper body fat depots could result from mild oxidative stress, cortisol activation and inflammation. The metabolic complications associated with lipodystrophy are responsible for increased cardiovascular and hepatic risks and could also participate in premature aging. We propose that adipose tissue injury by HIV and cART induces fat hypertrophy or atrophy and contributes to premature aging

Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection

International audienceTwo of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathway

The Oxygen Paradox, the French Paradox, and age-related diseases

open46openDavies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, Henry J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A.Davies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, HENRY J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A