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BACKGROUND: Although some integrase strand transfer inhibitors (INSTIs) promote peripheral and central adipose tissue/weight gain in people with human immunodeficiency virus (PHIV), the underlying mechanism has not been identified. Here, we used human and simian models to assess the impact of INSTIs on adipose tissue phenotype and function. METHODS: Adipocyte size and fibrosis were determined in biopsies of subcutaneous and visceral adipose tissue (SCAT and VAT, respectively) from 14 noninfected macaques and 19 PHIV treated or not treated with an INSTI. Fibrosis, adipogenesis, oxidative stress, mitochondrial function, and insulin sensitivity were assessed in human proliferating or adipocyte-differentiated adipose stem cells after long-term exposure to dolutegravir or raltegravir. RESULTS: We observed elevated fibrosis, adipocyte size, and adipogenic marker expression in SCAT and VAT from INSTI-treated noninfected macaques. Adiponectin expression was low in SCAT. Accordingly, SCAT and VAT samples from INSTI-exposed patients displayed higher levels of fibrosis than those from nonexposed patients. In vitro, dolutegravir and, to a lesser extent, raltegravir were associated with greater extracellular matrix production and lipid accumulation in adipose stem cells and/or adipocytes as observed in vivo. Despite the INSTIs' proadipogenic and prolipogenic effects, these drugs promoted oxidative stress, mitochondrial dysfunction, and insulin resistance. CONCLUSIONS: Dolutegravir and raltegravir can directly impact adipocytes and adipose tissue. These INSTIs induced adipogenesis, lipogenesis, oxidative stress, fibrosis, and insulin resistance. The present study is the first to shed light on the fat modifications observed in INSTI-treated PHIV.
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Infecções por HIV , Inibidores de Integrase de HIV , Resistência à Insulina , Adipócitos , Tecido Adiposo , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Inibidores de Integrase/uso terapêutico , Oxazinas , Piperazinas , Piridonas , Raltegravir Potássico/uso terapêuticoRESUMO
PURPOSE OF REVIEW: Antiretroviral therapy (ART) has long been implicated in fat alterations and weight variations leading to cardiometabolic consequences. Recent largely prescribed antiretrovirals (ARVs) from the integrase-strand-transfer-inhibitor (INSTI) class have been associated with excessive weight gain/obesity in a minority of persons with HIV (PWH). As well, in the nucleoside reverse transcriptase inhibitors (NRTI) class, tenofovir-alafenamide (TAF), often replacing tenofovir-disoproxil-fumarate (TDF), has been associated with weight gain, a worrying concern in the present worldwide obesogenic environment. The respective role of the different ARV, the risk factors and the mechanisms remain questionable. RECENT FINDINGS: The INSTIs dolutegravir (DTG) and bictegravir (BIC) and TAF have a proper effect on weight gain, while efavirenz (EFV) and TDF inhibit it. These effects are reported in ART-naïve PWH, in addition to weight gain resulting from the return to health process, and in ART-controlled PWH. Also, INSTIs induce weight gain in adolescents and excessive weight gain during pregnancy. The effects of INSTIs and TAF are additive. Their trajectory differs. Most of the weight gain is observed during the initial 12-month period.The main risk factors are low CD4+ and high viral load (VL) in ART-naïve PWH, Black race or originating from some African countries and female gender. The role of age and BMI differs between studies. The reversibility of the effect of INSTI and TAF appears limited.Regarding the mechanisms, the INSTIs can directly alter adipose tissue in particular through inhibition of fat beiging, resulting in fat fibrosis and hypertrophy. Macrophage infiltration is decreased. The mechanisms explaining the opposite effects of TDF and TAF remain elusive. SUMMARY: The specific impact of DTG, BIC and TAF on weight gain/obesity in PWH is confirmed in different populations independently of the weight limiting effect of EFV and TDF. ART-linked excessive weight gain is uncommon. African origin and female sex are risk factors that need to be considered. The mechanisms are better understood for INSTIs but unknown for TDF/TAF. The reversibility of weight gain/obesity when stopping INSTI or TAF remains limited.
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Fármacos Anti-HIV , Infecções por HIV , Aumento de Peso , Adolescente , Feminino , Humanos , Gravidez , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Infecções por HIV/tratamento farmacológico , Obesidade , Tenofovir/farmacologia , Aumento de Peso/efeitos dos fármacos , MasculinoRESUMO
HIV infection has been controlled only since the introduction of triple therapy in 1996, combining, as antiretroviral agents, two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI). However, among the NRTIs, the thymidine analogues stavudine and zidovudine led to lipoatrophy, either generalized or associated with visceral fat hypertrophy and buffalo hump. These molecules also increased insulin resistance and the prevalence of diabetes. They were replaced by other NRTIs or non-NRTIs (NNRTIs) that were considered to be free of adipose tissue (AT) toxicity. More recently, the NRTI tenofovir disoproxyfumarate (TDF) and the NNRTI efavirenz have been associated with inhibition of fat gain but not with clear lipoatrophy. Otherwise, the use of PIs led to a phenotype of trunk fat hypertrophy associated with cardiometabolic complications. To avoid their adverse effects, PIs have recently been replaced by a new class of antiretrovirals, the integrase inhibitors (INSTIs), which are well tolerated and effective in controlling HIV. However, this class has been associated with global weight gain, which may be important and concerning for some people living with HIV (PWH). Also, in the NRTI class, TDF has often been replaced by tenofovir alafenamide (TAF) due to bone and renal toxicities, and TAF has been associated with global fat gain. The cardiometabolic consequences of INTIs and TAF are primarily related to the associated weight gain. In the global obesogenic worldwide context, PWH are gaining weight as well in relation to poor health life conditions. Taking in charge obesity uses the same strategies as those used in the general population.
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Tecido Adiposo , Infecções por HIV , Humanos , Infecções por HIV/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Síndrome de Lipodistrofia Associada ao HIV/induzido quimicamente , Antirretrovirais/efeitos adversos , Antirretrovirais/uso terapêutico , Tenofovir/uso terapêutico , Tenofovir/efeitos adversosRESUMO
During chronic SIV/HIV infection, adipose tissue (AT) is the target of both antiretroviral treatment (ART) and the virus. AT might subsequently contribute to the low-grade systemic inflammation observed in patients on ART. To evaluate the inflammatory profile of AT during chronic SIV/HIV infection, we assayed subcutaneous and visceral abdominal AT from non-infected (SIV-, control), ART-naïve SIV-infected (SIV+) and ART-controlled SIV-infected (SIV+ART+) cynomolgus macaques for the mRNA expression of genes coding for factors related to inflammation. Significant differences were observed only when comparing the SIV+ART+ group with the SIV+ and/or SIV- groups. ART-treated infection impacted the metabolic fraction (with elevated expression of PPARγ and CEBPα), the extracellular matrix (with elevated expression of COL1A2 and HIF-1α), and the inflammatory profile. Both pro- and anti-inflammatory signatures were detected in AT, with greater mRNA expression of anti-inflammatory markers (adiponectin and CD163) and markers associated with inflammation (TNF-α, Mx1, CCL5 and CX3CL1). There were no intergroup differences in other markers (IL-6 and MCP-1). In conclusion, we observed marked differences in the immune and metabolic profiles of AT in the context of an ART-treated, chronic SIV infection; these differences were related more to ART than to SIV infection per se.
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Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Adiponectina , Tecido Adiposo/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , HIV , Inflamação/complicações , Interleucina-6 , Macaca fascicularis , Macaca mulatta , PPAR gama , RNA Mensageiro/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Fator de Necrose Tumoral alfaRESUMO
For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance.
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Inibidores de Integrase de HIV , Resistência à Insulina , Adipócitos/metabolismo , Tecido Adiposo , Amidas , Fibrose , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Hipertrofia/metabolismo , Hipóxia/metabolismo , Oxazinas , Piperazinas , PiridonasRESUMO
PURPOSE OF REVIEW: Increased total body fat with truncal redistribution is common in antiretroviral therapy (ART)-controlled persons living with HIV(PLWH), leading to insulin resistance, prediabetes/diabetes and dyslipidaemia. We address these topics here. RECENT FINDINGS: Most antiretrovirals are associated with gain in trunk fat, including visceral adipose tissue (VAT). Protease-inhibitors could inhibit white fat ability to dissipate energy (i.e. beiging) favouring fat gain. Expansion of VAT is associated with a pro-inflammatory profile linked to the tryptophan-kynurenine pathway and CD4+ subtypes. ART-associated increased adipose tissue (AT) quantity leads to decreased AT density, insulin resistance and dyslipidaemia that could be improved by lifestyle modifications.PLWH present high level of insulin resistance, regardless of their treatment, and a higher prevalence of prediabetes, but not diabetes, than noninfected persons. Otherwise, HbA1c values appear inaccurate to diagnose prediabetes/diabetes in PLWH.ART-related-dyslipidaemia is characterized by elevated LDL-C and/or high triglycerides and reduced HDL-C. Whereas treatment with protease inhibitors generally results in worsened lipid values, treatment with integrase-strand-transfer-inhibitors is associated with a better profile. Tenofovir-alafenamide is associated with higher lipid levels than tenofovir-disoproxil-fumarate. Treatment of LDL-C-dyslipidaemia could benefit, in statin-insufficiently controlled patients, from the class of proprotein-convertase-subtilsin-kenin-type-9 (PCSK-9) inhibitors. SUMMARY: Lifestyle modifications are mandatory to reduce fat and improve dysglycaemia/dyslipidaemia. New drugs can efficiently control diabetes and LDL-C-dyslipidaemia.
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Diabetes Mellitus , Dislipidemias , Infecções por HIV , Resistência à Insulina , Tecido Adiposo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , HumanosRESUMO
White adipose tissue (AT) contributes significantly to inflammation - especially in the context of obesity. Several of AT's intrinsic features favor its key role in local and systemic inflammation: (i) large distribution throughout the body, (ii) major endocrine activity, and (iii) presence of metabolic and immune cells in close proximity. In obesity, the concomitant pro-inflammatory signals produced by immune cells, adipocytes and adipose stem cells help to drive local inflammation in a vicious circle. Although the secretion of adipokines by AT is a prime contributor to systemic inflammation, the lipotoxicity associated with AT dysfunction might also be involved and could affect distant organs. In HIV-infected patients, the AT is targeted by both HIV infection and antiretroviral therapy (ART). During the primary phase of infection, the virus targets AT directly (by infecting AT CD4 T cells) and indirectly (via viral protein release, inflammatory signals, and gut disruption). The initiation of ART drastically changes the picture: ART reduces viral load, restores (at least partially) the CD4 T cell count, and dampens inflammatory processes on the whole-body level but also within the AT. However, ART induces AT dysfunction and metabolic side effects, which are highly dependent on the individual molecules and the combination used. First generation thymidine reverse transcriptase inhibitors predominantly target mitochondrial DNA and induce oxidative stress and adipocyte death. Protease inhibitors predominantly affect metabolic pathways (affecting adipogenesis and adipocyte homeostasis) resulting in insulin resistance. Recently marketed integrase strand transfer inhibitors induce both adipocyte adipogenesis, hypertrophy and fibrosis. It is challenging to distinguish between the respective effects of viral persistence, persistent immune defects and ART toxicity on the inflammatory profile present in ART-controlled HIV-infected patients. The host metabolic status, the size of the pre-established viral reservoir, the quality of the immune restoration, and the natural ageing with associated comorbidities may mitigate and/or reinforce the contribution of antiretrovirals (ARVs) toxicity to the development of low-grade inflammation in HIV-infected patients. Protecting AT functions appears highly relevant in ART-controlled HIV-infected patients. It requires lifestyle habits improvement in the absence of effective anti-inflammatory treatment. Besides, reducing ART toxicities remains a crucial therapeutic goal.
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Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Animais , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/imunologia , Obesidade/metabolismoRESUMO
Aging is associated with central fat redistribution and insulin resistance. To identify age-related adipose features, we evaluated the senescence and adipogenic potential of adipose-derived stromal cells (ASCs) from abdominal subcutaneous fat obtained from healthy normal-weight young (<25 years) or older women (>60 years). Increased cell passages of young-donor ASCs (in vitro aging) resulted in senescence but not oxidative stress. ASC-derived adipocytes presented impaired adipogenesis but no early mitochondrial dysfunction. Conversely, aged-donor ASCs at early passages displayed oxidative stress and mild senescence. ASC-derived adipocytes exhibited oxidative stress, and early mitochondrial dysfunction but adipogenesis was preserved. In vitro aging of aged-donor ASCs resulted in further increased senescence, mitochondrial dysfunction, oxidative stress, and severe adipocyte dysfunction. When in vitro aged young-donor ASCs were treated with metformin, no alteration was alleviated. Conversely, metformin treatment of aged-donor ASCs decreased oxidative stress and mitochondrial dysfunction resulting in decreased senescence. Metformin's prevention of oxidative stress and of the resulting senescence improved the cells' adipogenic capacity and insulin sensitivity. This effect was mediated by the activation of AMP-activated protein kinase as revealed by its specific inhibition and activation. Overall, aging ASC-derived adipocytes presented impaired adipogenesis and insulin sensitivity. Targeting stress-induced senescence of ASCs with metformin may improve age-related adipose tissue dysfunction.
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Adipócitos/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Metformina/farmacologia , Proteínas Quinases Ativadas por AMP , Adipócitos/metabolismo , Adipócitos/patologia , Envelhecimento/patologia , Células Cultivadas , Feminino , Humanos , Resistência à Insulina , Pessoa de Meia-Idade , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Adulto JovemRESUMO
An inability of adipose tissue to expand consequent to exhausted capacity to recruit new adipocytes might underlie the association between obesity and insulin resistance. Adipocytes arise from mesenchymal precursors whose commitment and differentiation along the adipocytic lineage is tightly regulated. These regulatory factors mediate cross-talk between adipose cells, ensuring that adipocyte growth and differentiation are coupled to energy storage demands. The WNT family of autocrine and paracrine growth factors regulates adult tissue maintenance and remodelling and, consequently, is well suited to mediate adipose cell communication. Indeed, several recent reports, summarized in this review, implicate WNT signalling in regulating adipogenesis. Manipulating the WNT pathway to alter adipose cellular makeup, therefore, constitutes an attractive drug-development target to combat obesity-associated metabolic complications.
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Adipogenia/genética , Proteínas Wnt/fisiologia , Adipogenia/fisiologia , Animais , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Humanos , Mediadores da Inflamação/fisiologia , Células-Tronco Mesenquimais/fisiologia , Modelos Biológicos , Obesidade/etiologia , Obesidade/genética , PPAR gama/fisiologia , Transdução de Sinais/genética , Proteínas Wnt/genética , beta Catenina/genética , beta Catenina/fisiologiaRESUMO
Human lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial fat loss, with fat hypertrophy in other depots when partial. Insulin resistance, dyslipidemia and diabetes are generally associated, leading to early complications. Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2(AGPAT2). Dominant partial familial lipodystrophies result from mutations in genes encoding the nuclear protein lamin A/C or the adipose transcription factor PPARgamma. Importantly, lamin A/Cmutations are also responsible for metabolic laminopathies, resembling the metabolic syndrome and progeria, a syndrome of premature aging. A number of lipodystrophic patients remain undiagnosed at the genetic level. Acquired lipodystrophy can be generalized, resembling congenital forms, or partial, as the Barraquer-Simons syndrome, with loss of fat in the upper part of the body contrasting with accumulation in the lower part. Although their etiology is generally unknown, they could be associated with signs of autoimmunity. The most common forms of lipodystrophies are iatrogenic. In human immunodeficiency virus-infected patients, some first-generation antiretroviral drugs were strongly related with peripheral lipoatrophy and metabolic alterations. Partial lipodystrophy also characterize patients with endogenous or exogenous long-term corticoid excess. Treatment of fat redistribution can sometimes benefit from plastic surgery. Lipid and glucose alterations are difficult to control leading to early occurrence of diabetic, cardiovascular and hepatic complications.
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Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Lipodistrofia , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Humanos , Lamina Tipo A/genética , Lipodistrofia/genética , Lipodistrofia/patologia , Lipodistrofia/fisiopatologia , PPAR gama/genéticaRESUMO
Early in the HIV epidemic, lipodystrophy, characterized by subcutaneous fat loss (lipoatrophy), with or without central fat accumulation (lipohypertrophy), was recognized as a frequent condition among people living with HIV (PLWH) receiving combination antiretroviral therapy. The subsequent identification of thymidine analogue nucleoside reverse transcriptase inhibitors as the cause of lipoatrophy led to the development of newer antiretroviral agents; however, studies have demonstrated continued abnormalities in fat and/or lipid storage in PLWH treated with newer drugs (including integrase inhibitor-based regimens), with fat gain due to restoration to health in antiretroviral therapy-naive PLWH, which is compounded by the rising rates of obesity. The mechanisms of fat alterations in PLWH are complex, multifactorial and not fully understood, although they are known to result in part from the direct effects of HIV proteins and antiretroviral agents on adipocyte health, genetic factors, increased microbial translocation, changes in the adaptive immune milieu after infection, increased tissue inflammation and accelerated fibrosis. Management includes classical lifestyle alterations with a role for pharmacological therapies and surgery in some patients. Continued fat alterations in PLWH will have an important effect on lifespan, healthspan and quality of life as patients age worldwide, highlighting the need to investigate the critical uncertainties regarding pathophysiology, risk factors and management.
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Distrofias Hereditárias da Córnea/diagnóstico , Distrofias Hereditárias da Córnea/terapia , Distrofias Hereditárias da Córnea/fisiopatologia , Gerenciamento Clínico , Humanos , Programas de Rastreamento/métodos , Microscopia com Lâmpada de Fenda/métodosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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BACKGROUND: Aging is characterized by adipose tissue senescence, inflammation, and fibrosis, with trunk fat accumulation. Aging HIV-infected patients have a higher risk of trunk fat accumulation than uninfected individuals-suggesting that viral infection has a role in adipose tissue aging. We previously demonstrated that HIV/SIV infection and the Tat and Nef viral proteins were responsible for adipose tissue fibrosis and impaired adipogenesis. We hypothesized that SIV/HIV infection and viral proteins could induce adipose tissue senescence and thus lead to adipocyte dysfunctions. METHODS: Features of tissue senescence were evaluated in subcutaneous and visceral adipose tissues of SIV-infected macaques and in human adipose stem cells (ASCs) exposed to Tat or Nef for up to 30 days. RESULTS: p16 expression and p53 activation were higher in adipose tissue of SIV-infected macaques than in control macaques, indicating adipose tissue senescence. Tat and Nef induced higher senescence in ASCs, characterized by higher levels of senescence-associated beta-galactosidase activity, p16 expression, and p53 activation vs. control cells. Treatment with Tat and Nef also induced oxidative stress and mitochondrial dysfunction. Prevention of oxidative stress (using N-acetyl-cysteine) reduced senescence in ASCs. Adipocytes having differentiated from Nef-treated ASCs displayed alterations in adipogenesis with lower levels of triglyceride accumulation and adipocyte marker expression and secretion, and insulin resistance. CONCLUSION: HIV/SIV promotes adipose tissue senescence, which in turn may alter adipocyte function and contribute to insulin resistance.
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Adipócitos/virologia , Tecido Adiposo/patologia , Senescência Celular , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Células-Tronco/virologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Acetilcisteína/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Animais , Senescência Celular/efeitos dos fármacos , Humanos , Resistência à Insulina , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Macaca fascicularis , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologiaRESUMO
Introduction: Efficient antiretroviral-treatment (ART) generally allows control of HIV infection. However, persons-living-with-HIV (PLWH), when aging, present a high prevalence of metabolic diseases. Area covered: Altered adiposity, dyslipidemias, insulin resistance, diabetes, and their consequences are prevalent in PLWH and could be partly related to ART. Expert opinion: At first, personal and lifestyle factors are involved in the onset of these complications. The persistence of HIV in tissue reservoirs could synergize with some ART and enhance metabolic disorders. Altered fat repartition, diagnosed as lipodystrophy, has been related to first-generation nucleoside-reverse-transcriptase-inhibitors (NRTIs) (stavudine zidovudine) and some protease inhibitors (PIs). Recently, use of some integrase-inhibitors (INSTI) resulted in weight/fat gain, which represents a worrisome unresolved situation. Lipid parameters were affected by some first-generation NRTIs, non-NRTIs (efavirenz) but also PIs boosted by ritonavir, with increased total and LDL-cholesterol and triglycerides. Insulin resistance is common associated with abdominal obesity. Diabetes incidence, high with first-generation-ART (zidovudine, stavudine, didanosine, indinavir) has declined with contemporary ART close to that of the general population. Metabolic syndrome, a dysmetabolic situation with central obesity and insulin resistance, and liver steatosis are common in PLWH and could indirectly result from ART-associated fat gain and insulin resistance. All these dysmetabolic situations increase the atherogenic cardiovascular risk.
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Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Doenças Metabólicas/induzido quimicamente , Tecido Adiposo/efeitos dos fármacos , Fármacos Anti-HIV/administração & dosagem , Dislipidemias/induzido quimicamente , Dislipidemias/epidemiologia , Glucose/metabolismo , Humanos , Estilo de Vida , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVE: HIV-infected patients receiving antiretroviral treatment (ART) often present adipose tissue accumulation and/or redistribution. adipose tissue has been shown to be an HIV/SIV reservoir and viral proteins as Tat or Nef can be released by infected immune cells and exert a bystander effect on adipocytes or precursors. Our aim was to demonstrate that SIV/HIV infection per se could alter adipose tissue structure and/or function. DESIGN: Morphological and functional alterations of subcutaneous (SCAT) and visceral adipose tissue (VAT) were studied in SIV-infected macaques and HIV-infected ART-controlled patients. To analyze the effect of Tat or Nef, we used human adipose stem cells (ASCs) issued from healthy donors, and analyzed adipogenesis and extracellular matrix component production using two dimensional (2D) and three-dimensional (3D) culture models. METHODS: Adipocyte size and index of fibrosis were determined on Sirius red-stained adipose tissue samples. Proliferating and adipocyte 2D-differentiating or 3D-differentiating ASCs were treated chronically with Tat or Nef. mRNA, protein expression and secretion were examined by RT-PCR, western-blot and ELISA. RESULTS: SCAT and VAT from SIV-infected macaques displayed small adipocytes, decreased adipogenesis and severe fibrosis with collagen deposition. SCAT and VAT from HIV-infected ART-controlled patients presented similar alterations. In vitro, Tat and/or Nef induced a profibrotic phenotype in undifferentiated ASCs and altered adipogenesis and collagen production in adipocyte-differentiating ASCs. CONCLUSION: We demonstrate here a specific role for HIV/SIV infection per se on adipose tissue fibrosis and adipogenesis, probably through the release of viral proteins, which could be involved in adipose tissue dysfunction contributing to cardiometabolic alterations of HIV-infected individuals.
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Adipogenia/efeitos dos fármacos , Tecido Adiposo/patologia , Fibrose/patologia , Infecções por HIV/patologia , HIV/crescimento & desenvolvimento , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Adulto , Animais , Células Cultivadas , Feminino , Produtos do Gene nef/metabolismo , Produtos do Gene tat/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Síndrome de Imunodeficiência Adquirida dos Símios/patologiaRESUMO
Although white AT can contribute to anti-infectious immune responses, it can also be targeted and perturbed by pathogens. The AT's immune involvement is primarily due to strong pro-inflammatory responses (with both local and paracrine effects), and the large number of fat-resident macrophages. Adipocytes also exert direct antimicrobial responses. In recent years, it has been found that memory T cells accumulate in AT, where they provide efficient secondary responses against viral pathogens. These observations have prompted researchers to re-evaluate the links between obesity and susceptibility to infections. In contrast, AT serves as a reservoir for several persistence pathogens, such as human adenovirus Ad-36, Trypanosoma gondii, Mycobacterium tuberculosis, influenza A virus, and cytomegalovirus (CMV). The presence and persistence of bacterial DNA in AT has led to the concept of a tissue-specific microbiota. The unexpected coexistence of immune cells and pathogens within the specific AT environment is intriguing, and its impact on anti-infectious immune responses requires further evaluation. AT has been recently identified as a site of HIV persistence. In the context of HIV infection, AT is targeted by both the virus and the antiretroviral drugs. AT's intrinsic metabolic features, large overall mass, and wide distribution make it a major tissue reservoir, and one that may contribute to the pathophysiology of chronic HIV infections. Here, we review the immune, metabolic, viral, and pharmacological aspects that contribute to HIV persistence in AT. We also evaluate the respective impacts of both intrinsic and HIV-induced factors on AT's involvement as a viral reservoir. Lastly, we examine the potential consequences of HIV persistence on the metabolic and immune activities of AT.
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OBJECTIVES: Adipose tissue from patients with HIV-related lipodystrophy presents a state of chronic inflammation. Altered expression of cytokines/adipokines and macrophage infiltration could be involved in patients' insulin resistance and lipoatrophy. We tested whether antiretrovirals affected adipokine release by human subcutaneous adipocytes and cytokine/chemokine production by human macrophages and examined whether reactive oxygen species (ROS) hyperproduction was related to the effect of antiretrovirals. METHODS: Differentiated human adipocytes and PMA-THP-1 macrophages were treated with protease inhibitors (PIs: indinavir, nelfinavir, amprenavir, lopinavir, ritonavir and atazanavir) or nucleoside reverse transcriptase inhibitors (NRTIs: stavudine, zidovudine and abacavir) for 24-48 h without or with diphenylene iodonium (DPI), an inhibitor of oxidative stress. Lipid content was assessed by Oil Red O staining and ROS production by nitroblue tetrazolium (NBT) reduction. Cytokine/chemokines, adiponectin and leptin release was evaluated by ELISA or multiplex assays. RESULTS: In human adipocytes, PIs and NRTIs (except amprenavir, atazanavir and abacavir) reduced lipid content, adiponectin and leptin release and increased in parallel ROS production and monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 release. The effects of PIs, but not of NRTIs, were prevented by the addition of DPI. In PMA-THP-1 macrophages, all PIs, but no NRTI, increased macrophage inflammatory protein-1 alpha and MCP-1 release. Lopinavir, nelfinavir, zidovudine and stavudine markedly increased ROS production and release of IL-1 beta and tumour necrosis factor-alpha. CONCLUSIONS: Some PIs altered adipokine secretion and lipid content through ROS production in human subcutaneous adipocytes. Thymidine analogues altered adipocyte functions but their effect on adipokine secretion was not reverted by ROS production inhibition. Increased chemokine/cytokine production by adipocytes and macrophages could be involved in macrophage recruitment and participate in lipoatrophy and insulin resistance.
Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Inibidores da Protease de HIV/farmacologia , Macrófagos/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Adipócitos/metabolismo , Adiponectina/metabolismo , Linhagem Celular , Quimiocinas/metabolismo , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Síndrome de Lipodistrofia Associada ao HIV/fisiopatologia , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
: The increased prevalence of age-related comorbidities and mortality is worrisome in ageing HIV-infected patients. Here, we aim to analyse the different ageing mechanisms with regard to HIV infection. Ageing results from the time-dependent accumulation of random cellular damage. Epigenetic modifications and mitochondrial DNA haplogroups modulate ageing. In antiretroviral treatment-controlled patients, epigenetic clock appears to be advanced, and some haplogroups are associated with HIV infection severity. Telomere shortening is enhanced in HIV-infected patients because of HIV and some nucleoside analogue reverse transcriptase inhibitors. Mitochondria-related oxidative stress and mitochondrial DNA mutations are increased during ageing and also by some nucleoside analogue reverse transcriptase inhibitors. Overall, increased inflammation or 'inflammageing' is a major driver of ageing and could result from cell senescence with secreted proinflammatory mediators, altered gut microbiota, and coinfections. In HIV-infected patients, the level of inflammation and innate immunity activation is enhanced and related to most comorbidities and to mortality. This status could result, in addition to age, from the virus itself or viral protein released from reservoirs, from HIV-enhanced gut permeability and dysbiosis, from antiretroviral treatment, from frequent cytomegalovirus and hepatitis C virus coinfections, and also from personal and environmental factors, as central fat accumulation or smoking. Adaptive immune activation and immunosenescence are associated with comorbidities and mortality in the general population but are less predictive in HIV-infected patients. Biomarkers to evaluate ageing in HIV-infected patients are required. Numerous systemic or cellular inflammatory, immune activation, oxidative stress, or senescence markers can be tested in serum or peripheral blood mononuclear cells. The novel European Study to Establish Biomarkers of Human Ageing MARK-AGE algorithm, evaluating the biological age, is currently assessed in HIV-infected patients and reveals an advanced biological age. Some enhanced inflammatory or innate immune activation markers are interesting but still not validated for the patient's follow-up. To be able to assess patients' biological age is an important objective to improve their healthspan.
Assuntos
Envelhecimento/patologia , Biomarcadores/análise , Infecções por HIV/patologia , Pesquisa Biomédica/tendências , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Inflamação/fisiopatologiaRESUMO
It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.
Assuntos
Tecido Adiposo/imunologia , Diabetes Mellitus Tipo 2/complicações , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos , Obesidade/complicações , Adiponectina/biossíntese , Adiponectina/sangue , Diabetes Mellitus Tipo 2/imunologia , Humanos , Inflamação/complicações , Inflamação/imunologia , Interleucina-6/biossíntese , Interleucina-6/sangue , Leptina/biossíntese , Leptina/sangue , Macrófagos/imunologia , Obesidade/imunologia , Resistina/biossíntese , Resistina/sangue , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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 (TNFalpha, 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.