Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.16 (HIV-1 protease)
2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibitory effect of alpha 2-macroglobulin (alpha 2M), a major plasma proteinase inhibitor, on human immunodeficiency virus (HIV) proteinase was investigated. The activity of HIV proteinase toward the Moloney murine sarcoma virus-derived gag protein (a high-molecular-mass substrate) was found to be inhibited by alpha 2M at pH 5.5-7.4. On the other hand, the activity toward the B chain of oxidized insulin (a low-molecular-mass substrate) was scarcely inhibited. The complex of alpha 2M and HIV proteinase was isolated by gel filtration and the enzyme was shown to be significantly protected by the complex formation from autoinactivation under nonreducing conditions. The stoichiometry of the complex formation was found to be 2:1 (enzyme: alpha 2M, mol/mol). These results demonstrate the entrapment and concomitant inhibition of HIV proteinase by alpha 2M.
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PMID:Entrapment and inhibition of human immunodeficiency virus proteinase by alpha 2-macroglobulin and structural changes in the inhibitor. 769 Mar 56

HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndrome's pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome.
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PMID:Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. 965 87

Multidrug antiretroviral regimens that include human immunodeficiency virus-1 (HIV-1) protease inhibitors are associated with distinct lipodystrophy, hypertriglyceridemia, hyperinsulinemia, and deposition of visceral abdominal adipose tissue. To determine whether these findings are related to abnormalities of adrenal function, we compared the hypothalamic-pituitary-adrenal axes of HIV-positive patients who had evidence of protease inhibitor-associated lipodystrophy (PIAL), control volunteers (CON), and patients with Cushing's syndrome (CS). To elucidate the metabolic consequences of the observed lipodystrophy, we measured basal serum lipids and compared glucose and insulin concentrations during an oral glucose tolerance test. Spontaneous plasma cortisol showed normal diurnal variation in PIAL. Cortisol levels were similar in CON and PIAL, and levels in these groups were less than those in CS at all times of the night or day (P < 0.005). Ovine CRH-stimulated morning plasma cortisol levels were similar in PIAL and CON. ACTH was significantly greater in PIAL than CON (P < 0.05) at 0, 15, and 30 min after CRH stimulation. Urinary free cortisol in PIAL (mean +/- SD, 76 +/- 51 nmol/day) was significant lower than those in CON (165 +/- 64 nmol/day; P < 0.001) and CS (1715 +/- 1203 nmol/day; P < 0.001). However, 17-hydroxycorticosteroid excretion was significantly greater in PIAL (43 +/- 23 micromol/day) than in CON (17 +/- 8 micromol/day; P < 0.001), although lower than that in CS (74 +/- 47 micromol/day; P < 0.01). Scatchard analysis revealed normal glucocorticoid receptor number and affinity in PIAL. Serum triglycerides were significantly greater in PIAL (6.57 +/- 5.63 mmol/L) than in CS (1.78 +/- 0.83 mmol/L; P < 0.001) or CON (1.36 +/- 0.84 mmol/L; P < 0.001). Although triglyceride levels were significantly correlated with body mass index for CON and CS, these were not correlated for PIAL. During an oral glucose tolerance test, similar glucose and insulin values were found in PIAL and CS that were greater (P < 0.05) than CON values at 30, 60, 90, and 120 min. We conclude that the lipodystrophy associated with use of HIV-1 protease inhibitors is a syndrome of increased intraabdominal adiposity with concomitant dyslipidemia and insulin resistance, but without total body weight gain and is distinct from any known form of hypercortisolism. Although urinary cortisol disposition seems to be altered in HIV-infected patients who are being treated with multidrug regimens that include protease inhibitors, the decreased free cortisol and increased 17-hydroxycorticosteroid excretion appear to be unlikely explanations for the observed lipodystrophy. The cause remains to be elucidated.
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PMID:Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy. 1037 88

HIV-positive patients receiving antiretroviral therapy with HIV-1 protease-inhibitors (PI) frequently show insulin-resistance, impaired glucose tolerance, hypertriglyceridaemia and lipodystrophy (LD). LD has often been reported only after the beginning of PI therapy. Some authors link LD to HIV chronic infection, some others suggest that PIs increase pre-existent disturb. Preliminary data of an observational study drawn in IV day-hospital of Spallanzani Institute in Rome showed hypertriglyceridaemia in 36.4% and hyperglycaemia in 11.2% of patients treated with PI. Carr suggests that such drugs should have this lipid-increasing effect because of their inhibition of low density lipoprotein-receptor-related protein, cytoplasmic retinoic-acid binding protein type 1 and P450 3A cytochrome. This theory doesn't explain why both untreated patients and treated with only reverse transcriptase inhibitors show sometimes the same disorders. According to another hypothesis Tumor necrosis factor-alpha, through inhibition of lipoprotein-lipase, would determine high fat-storage in the adipose tissue. Cardiovascular risk factors have always to be assessed before starting a therapy with PI. Glycaemia, triglyceridaemia, cholesterolaemia have to be performed every three months during the treatment and, if necessary, C-Peptide and insulinaemia too. A treatment with lipid-lowering drugs is always recommended in patients with hypertriglyceridaemia > 500 mg/dl and/or hypercholesterolaemia LDL > 190 mg/dl in two following checks. Fibrates have proven to be effective in reducing hypertriglyceridaemia, but there is no certainty that such therapies could have good effects on the LD itself too.
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PMID:[Dysmetabolic syndrome related to HIV-1 protease inhibitors. Review of the literature and personal data]. 1074 53

Since the introduction of HIV-1 protease inhibitors as components of antiretroviral drug combination regimens, the clinical course of HIV disease and opportunistic infections has changed dramatically. Besides the favourable virological, immunological and clinical impact of highly active antiretroviral therapy (HAART), several adverse drug reactions have been observed in patients with HIV receiving therapy. Particularly, peripheral lipodystrophy, central adiposity, dyslipidaemia and insulin resistance have been described with a prevalence of up to 80% in patients infected with HIV, and attributed to almost all components of HAART. Hyperlipidaemia is characterised by an increase of low and very low density lipoprotein-cholesterol as well as apolipoproteins B and E. Several studies strongly suggest that there are either multiple syndromes or a variety of factors inducing different changes that influence the ultimate phenotype. Similarities between HIV-associated fat redistribution and metabolic abnormalities with both inherited lipodystrophies and benign symmetric lipomatosis suggest the pathophysiological involvement of, for example, nuclear factors like lamin A/C and drug-induced mitochondrial dysfunction. Moreover, there is some evidence that cytokines and hormones impair fat and glucose homeostasis in patients with HIV receiving HAART. Three years after the first description of HIV therapy-associated abnormal fat redistribution, there is still an ongoing discussion about the case definition, diagnostic procedure and treatment options for both body shape changes and metabolic disturbances. Regarding therapy, there is a major concern about possible complex pharmacological interactions and overlapping adverse effects between HAART and, for example, lipid-lowering therapy. In addition, the likely contribution of both nucleoside analogue reverse transcriptase inhibitors and protease inhibitors to the development of abnormal fat redistribution in patients with HIV limits options of changing to alternative effective antiretroviral drug combinations. Thus, the occurrence of hyperlipidaemia, maturity onset diabetes mellitus, and marked changes in body habitus resulted in important social and clinical consequences such as an increased risk of atherosclerosis. It also sheds new light on the use of protease inhibitors regarding risk factors for the initial treatment decision. In this article, we discuss the features, pathogenesis and treatment options for body fat redistribution and metabolic disturbances associated with HAART in HIV-1 infection.
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PMID:Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed? 1091 32

We prospectively followed 20 consecutive patients with human immunodeficiency virus type 1 (HIV-1) with viral loads of <200 RNA copies/mL. These patients had been treated with 2 nucleoside reverse transcriptase inhibitors and > or =1 HIV-1 protease inhibitor for > or =3 months; they developed body changes consistent with lipodystrophy and requested they be switched from protease inhibitor to efavirenz. At baseline and every 3 months, we assessed the following: body mass index, waist-to-hip ratio, regional fat thickness (assessed by sonography), fasting total and high-density lipoprotein cholesterol, triglycerides, glucose, insulin, CD4(+) cells, and viral load. At baseline, hypertriglyceridemia (> or =200 mg/dL) was present in 17 (85%) patients, hypercholesterolemia (> or =200 mg/dL) in 14 (70%), and impaired fasting glucose (> or =110 mg/dL) in 8 (40%); CD4(+) T cells were 280x10(6) cells/L (range, 64-942x10(6) cells/L). HIV-1 RNA had been at <200 copies/mL for a median of 14 months (range, 3-24 months). Six months after switching to efavirenz, there was a reduction in triglyceride levels (a decrease of 31%; P=.03) and fasting insulin resistance index (a decrease of 28%; P=.03), but total and high-density lipoprotein cholesterol and glucose did not change. Waist-to-hip ratio decreased from 0.92 to 0.87 (P=.06). Subcutaneous fat thickness did not change. CD4(+) cells remained stable (363x10(6) cells/L; range, 102-741x10(6) cells/L; P=.65). Nineteen patients (95%) had HIV-1 RNA levels that remained at <200 copies/mL. Although CD4(+) response and viral suppression remained preserved after 6 months of switching from protease inhibitor to efavirenz, the benefits of this approach on the evolution of lipodystrophy were limited, and our findings do not support its routine recommendation to treat lipodystrophy.
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PMID:Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. 1107 62

New-onset diabetes mellitus, clinically similar to type 2 diabetes, will affect a small proportion (1%-6%) of patients infected with human immunodeficiency virus (HIV) who are treated with HIV-1 protease inhibitors (PIs). However, insulin resistance and impaired glucose tolerance will develop during PI treatment in a considerable proportion of patients. Dyslipidemia, abdominal obesity, and loss of peripheral fat frequently coexist with insulin resistance, but it is not clear whether all of these result from a common pathogenic mechanism. Recent data suggest that insulin resistance may also be associated with HIV infection in patients not receiving PI therapy. The long-term consequences of insulin resistance in this population are not known. The effect of switching to other antiretroviral therapies has not been fully determined. Treatment of established diabetes mellitus should generally follow existing guidelines. There is no clinically useful screening test that will determine the existence and degree of insulin resistance in individual patients. It is therefore reasonable to recommend general measures to increase insulin sensitivity in all patients infected with HIV, such as weight reduction for obese persons and regular aerobic exercise.
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PMID:Disorders of glucose metabolism in patients infected with human immunodeficiency virus. 1109 14

The lipodystrophies are rare disorders characterized by selective but variable loss of adipose tissue. Metabolic complications, such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver, increase in severity with the extent of fat loss. The lipodystrophies can be classified into two major types: familial and acquired. The main subtypes of familial lipodystrophies are congenital generalized lipodystrophy, an autosomal recessive disorder characterized by near complete lack of metabolically active adipose tissue from birth, and familial partial lipodystrophy, Dunnigan type, an autosomal dominant disorder characterized by loss of subcutaneous fat from the extremities at puberty and excess fat accumulation in the face and neck. Recently, a gene for congenital generalized lipodystrophy was localized to chromosome 9q34, and a gene for familial partial lipodystrophy, Dunnigan type, to chromosome 1q21-22; the genes, however, remain to be identified. Patients with acquired generalized lipodystrophy have generalized loss of subcutaneous fat, but those with acquired partial lipodystrophy have fat loss limited to the face, trunk, and upper extremities. Both varieties occur approximately three times more often in women, begin during childhood, and have underlying autoimmunity. Patients infected with the human immunodeficiency virus (HIV) who are receiving therapy that includes HIV-1 protease inhibitors have been reported to develop a lipodystrophy characterized by loss of subcutaneous fat from the extremities and face but excess fat deposition in the neck and trunk. Localized lipodystrophies can be caused by drugs, pressure, panniculitis, or unknown mechanisms. Current management of patients includes cosmetic surgery, diet, and drug therapy for control of diabetes and dyslipidemia.
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PMID:Lipodystrophies. 1112 8

Long-term use of HIV-1 protease inhibitors (PIs) is associated with a lipodystrophy syndrome. To delineate the associated mechanisms, adipogenesis was determined in 3T3-L1 cells in the presence or absence of either indinavir (2-50 microg/ml) or ritonavir (0.4-10 microg/ml). A concentration-dependent decrease in both lipid (4-59%) and triglyceride (11-49%) levels was seen after 10 days of exposure. Simultaneous treatment with TNF-alpha showed a synergistic suppression in lipid levels by 45-95% at 10 U/ml and almost complete suppression at 100 U/ml. The effect of PIs on insulin-induced lipogenesis was monitored by [(14)C)]glucose incorporation into lipids, which was suppressed by 21-86% in a concentration-dependent manner. Insulin-sensitizing agent, troglitazone (80 and 400 nM), effectively blocked the PI-mediated adipogenic suppression. Preadipocyte factor 1 gene (pref-1) expression, as monitored by RT-PCR, was downregulated (4- to 6-fold) within 48 hr after insulin stimulation; however, a smaller decrease (1.2- to 1.8-fold) was observed in PI-exposed cells. The decrease in proteolytic activity of matrix metalloproteases (MMP-2 and MMP-9) during adipogenesis was reversed on exposure to the PIs. Similarly, the plasminolytic activity was increased and plasminogen activator inhibitor (PAI) activity was decreased in supernatants from PI-treated cells. The insulin-mediated induction (3- to 4-fold) of PAI-1 and PAI-2 message was suppressed on exposure to PIs, which was reversed by troglitazone treatment. Thus, the HIV-1 PIs may suppress adipogenesis by disrupting the concerted actions of host proteases that regulate ECM integrity required for initiation of differentiation.
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PMID:Synergistic antiadipogenic effects of HIV type 1 protease inhibitors with tumor necrosis factor alpha: suppression of extracellular insulin action mediated by extracellular matrix-degrading proteases. 1177 45

Human immunodeficiency virus (HIV) infection is a major global health problem. Recently, combination therapy including HIV-1 protease inhibitors (PIs) has dramatically improved the long-term survival of HIV-infected patients. However, such therapy is associated with a lipodystrophy syndrome characterized by selective loss of sc fat from the face and extremities and, in some patients, accumulation of fat around the neck, dorsocervical region, abdomen, and trunk. Lipodystrophy in HIV-infected patients (LDHIV) is associated with insulin resistance and its metabolic complications such as impaired glucose tolerance, diabetes, hypertriglyceridemia and low serum high density lipoprotein cholesterol levels. PIs appear to be the strongest link to LDHIV; however, fat loss has been reported in some patients taking non-PI antiretroviral drugs. Other factors, such as duration of HIV infection, age, and gender, may also contribute to the risk of development of LDHIV. The molecular basis of LDHIV remains unknown. There is no specific therapy for LDHIV. Avoiding weight gain by reducing energy intake and increasing physical activity may be beneficial in reducing fat accumulation as well as improving metabolic complications. Antihyperglycemic drugs may be used to treat diabetes. Management of dyslipidemia may require lipid-lowering drugs; however, the safety and efficacy of such intervention require further studies. Substitution of PIs with other antiretroviral drugs can mitigate dyslipidemia and glucose intolerance, but whether reversal of lipodystrophy occurs remains unknown. Future research is needed to discover the biochemical and molecular markers of lipodystrophy in HIV patients and develop PIs or other antiretroviral agents that are free of metabolic toxicity.
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PMID:Clinical review 153: Lipodystrophy in human immunodeficiency virus-infected patients. 1241 37


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