Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipodystrophies, characterized by reduction of subcutaneous fat over part or all of the body surface, are uncommon. Their causes are unknown. Recently, lipodystrophy has been reported in human immunodeficiency virus (HIV)-infected patients taking protease inhibitors, which have been recommended since 1996 as standard therapy for HIV disease in combination with nucleoside analogues. In these cases, lipodystrophy consists of an association of peripheral lipoatrophy with central adiposity. We report four HIV-infected men on protease inhibitors who developed a disfiguring lipodystrophy. In three of them, the protease inhibitor was administered for a mean duration of 21.5 months (range 19-23) with good immunological and virological responses. Patient 4 had been treated for 2 years with successive combinations of protease inhibitors with nucleoside analogues without success. The four patients progressively developed an increase in abdominal girth associated with fat wasting of the face and legs. Two of them had recurrent paronychia of the great toes. Triglyceride levels were moderately increased in all patients, and one had a slightly increased cholesterol level. One patient had elevated glucose and insulin plasma levels during a glucose tolerance test. In two patients, a deep biopsy taken from the thigh showed thinning of the subcutaneous fat without other morphological changes. Computed tomographic scans of the face and abdomen confirmed the loss of almost all subcutaneous fat of the cheek and temporal regions, and abdominal perivisceral fat accumulation. For patients 1-3, the protease inhibitor was replaced by a non-nucleoside reverse transcriptase inhibitor. Nine months later, dysmorphic changes had not regressed, but lipid abnormalities had returned to normal and the paronychia had disappeared.
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PMID:Lipodystrophy associated with protease inhibitors. 1073 57

Although effective treatment of antiretroviral-associated metabolic abnormalities ultimately depends on understanding the mechanisms involved, clinicians facing these problems are beginning to feel compelled to do something now to manage treatment-related metabolic complications. Diet and exercise should not be overlooked, because both can be effective in managing these complications without causing further side effects. Fibric acid derivatives such as gemfibrozil and statins can lower HIV-associated cholesterol and triglyceride levels, although further data are needed on problematic interactions between statins and protease inhibitors (PIs). Hypoglycemic agents may have some role in managing glucose abnormalities, although troglitazone cannot be recommended for fat abnormalities alone and metformin may cause lactic acidosis. Growth hormone and anabolic steroids may have some role in treating lipodystrophy, but the cost of growth hormone is prohibitive for many patients and definitive data on efficacy are lacking. Replacing a PI with a reverse transcriptase inhibitor has improved lipid and glucose levels in some studies. However, that strategy begs the question of how the nucleosides might contribute to lipodystrophy.
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PMID:How to manage metabolic complications of HIV therapy: what to do while we wait for answers. 1075 16

Retroviral protease inhibitors used as therapy for HIV-1 infection have been causally associated with serious metabolic side effects, including peripheral lipodystrophy, hyperlipidemia, insulin resistance, and in some cases, overt type 2 diabetes. The etiology of this characteristic clinical syndrome remains unknown. We demonstrate that the HIV protease inhibitor, indinavir, dramatically inhibits insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner (63% inhibition observed with 100 micrometer indinavir). Indinavir treatment did not affect early insulin signaling events or the translocation of intracellular Glut1 or Glut4 glucose transporters to the cell surface. To determine whether indinavir may be directly affecting the intrinsic transport activity of glucose transporters, the Glut1 and Glut4 isoforms were heterologously expressed and analyzed in Xenopus laevis oocytes. Indinavir at 100 microm had no effect on Glut1 transport activity in Xenopus oocytes, whereas Glut4 activity was significantly inhibited (45% inhibition). Similar effects on glucose transport were observed for other HIV protease inhibitors. We conclude that HIV protease inhibitors as a class are capable of selectively inhibiting the transport function of Glut4 and that this effect may be responsible for a major iatrogenic complication frequently observed in HIV patients.
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PMID:The mechanism of insulin resistance caused by HIV protease inhibitor therapy. 1080 89

Antiretroviral therapy (ART) is frequently associated with metabolic alterations, including insulin resistance and diabetes mellitus. In this pilot study, we evaluated the effect of the PPARgamma activator troglitazone on ART-associated insulin resistance in HIV-infected patients with ART-associated diabetes mellitus. Six patients with protease inhibitor (PI)-associated diabetes mellitus, lipodystrophy and dyslipidemia were treated with troglitazone 400 mg q.d. for 3 months. Previous oral antidiabetics were discontinued prior to the study. At baseline and after 3 months, insulin sensitivity (intravenous insulin tolerance test), body composition (multifrequence bioelectrical impedance analysis) and fat distribution (CT scan quantification) were assessed. Glycaemic control (fasting and postprandial blood glucose, fructosamine, glycosylated haemoglobin) and serum lipid status were determined monthly. In four of the six patients, there was a clear improvement in insulin sensitivity, resulting in a reversal of insulin resistance in two of these patients. Overall, there was an increase in lean body mass and a decrease in total body fat. The volume of visceral adipose tissue decreased whilst the volume of subcutaneous adipose tissue increased. Total cholesterol, LDL and HDL cholesterol increased, and total triglycerides and VLDL-cholesterol decreased. No adverse effects such as hepatotoxicity were observed. Treatment with troglitazone 400 mg q.d. can ameliorate and in some cases even reverse ART-associated insulin resistance. Therefore, further studies including non-diabetic patients with ART-associated insulin resistance may be helpful in evaluating the long-term effects of thiazolidinediones on ART-associated insulin resistance and other metabolic complications, such as adipose maldistribution and dyslipidaemia.
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PMID:Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus. 1081 54

For the effective treatment of HIV infection, combinations of antiretroviral drugs that, at various points of attack, prevent viral replication are used. After the introduction of HIV-1 specific protease inhibitors, various metabolic complications and changes in body habitus manifesting as abnormal fat distribution were observed in HIV patients. These side effects, initially assigned class-specifically to the protease inhibitors, have, however, also been frequently seen under other drug combinations. Changes to body habitus as a result of fat redistribution have mostly been designated as lipodystrophy syndrome, but are now increasingly being recognized as highly heterogeneous abnormalities. Furthermore, the disturbances of glucose and fat metabolism may occur completely independently of phenotypic habitus changes. The result is that both the suspected pathophysiological relationships and the therapeutic consequences are becoming even more complex. This paper summarizes the current state of investigations into the side effects of antiretroviral therapy and their clinical consequences.
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PMID:[Lipodystrophy and metabolic disorders in anti-HIV therapy]. 1086 18

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

Caffeoylglucosides, which have a glucose ring as a central linker, were synthesized from methyl D-glucosides, and their anti-HIV-1 activities were tested. Among them, four dicaffeoylglucosides (IC50 = 29.1+/-35.1 microM), 6a, 6b, 9b and 10b, showed HIV-1 integrase inhibitory activity as potent as L-chicoric acid.
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PMID:Synthesis and HIV-1 integrase inhibitory activities of caffeoylglucosides. 1096 90

We investigated longitudinally the effect of protease inhibitors (PI) on insulin sensitivity, glycemia, and serum lipids in HIV-infected patients. Ninety-one consecutive patients treated with PI for at least 12 months were included in this study. Fasting glycemia, lipid profile, insulinemia, CD4 T lymphocytes, and plasma HIV-1 RNA were performed at baseline and on PI therapy. Insulin sensitivity and insulin secretion were measured by the homeostasis model assessment (HOMA MODEL) using the fasting glucose and insulin concentrations. Triglycerides (+ 0.34 mmol/l, SD = 1.07, p = 0.001) and cholesterol (+ 1.07 mmol/l, SD = 1.21, p= 0.001) significantly increased on PI therapy. Fasting glycemia, insulin sensitivity, and insulin secretion were not modified after PI therapy. PI therapy significantly increased body mass index (0.35 kg/m2, p < 0.05). Serum lipid changes correlated with changes in the CD4+ cell count. Lipodystrophy was observed in 40.6% of patients treated with PI. Our longitudinal study found that PI therapy had no major impact on fasting glycemia, insulin sensitivity, and insulin secretion. These findings are not consistent with previous cross-sectional studies, which did not include baseline measurements before PI initiation. However, we observed a similar profile of lipid changes induced by PI therapy. These results suggest that PI could be responsible for the development of hypertriglyceridemia by a mechanism independent of insulin resistance which remains to be elucidated.
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PMID:HIV-1 protease inhibitors induce an increase of triglyceride level in HIV-infected men without modification of insulin sensitivity: a longitudinal study. 1101 86

Background: Cases of lipodystrophy syndrome and metabolic disorders have been described since the onset of highly active antiretroviral therapy in HIV-infected patients. The aim of our study was to estimate the prevalence of lipodystrophy (LD) and to define the associated lipid profile of these patients. Methods: The following were determined for each patient: lipid profile (cholesterol and its subfractions, atherogenicity ratios, and triglycerides), blood glucose, and immunovirological markers (CD4(+) cell count and plasma viral load). Patients were classified into two groups on the basis of whether or not they presented with clinical signs of LD. Results: Among 233 HIV-infected patients included in the study, 61 cases (26.1%) of lipodystrophy (LD) were noted. Compared with non-LD patients (NLD), LD patients were older men (P<10(-4)) with a lower CD4(+) lymphocyte cell count (P<0.007) and more often at the AIDS stage (P<10(-3)) (OR=3.2 (95% CI: 1.47-6.2)). Multivariate analysis showed a correlation between LD cases and age (10 years older) (OR=1.78 (95% CI: 1.23-2.57), P<0.002) and the decrease in CD4(+) cell count (100 CD4(+)/mm(3) lower) (OR=1.31 (95% CI: 1.09-1.58), P<0.004). An analysis of lipid subfractions and atherogenicity ratios clearly indicated a proatherogenic lipid profile for the LD patients. Conclusions: The underlying physiopathological mechanism of LD is still unknown. However, the lipid profile of HIV-1-infected patients with a LD syndrome appears to place these patients at an increased risk of progression of atherosclerosis.
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PMID:Atherogen lipid profile in HIV-1-infected patients with lipodystrophy syndrome. 1102 50

HIV (human immunodeficiency virus)-1 Env is displayed on the surface of infected cells and subsequently incorporated into virions, which is necessary for the initiation of a viral infection by recognition of the CD4 and the chemokine receptors (such as CCR5 or CXCR4) on the surface of new target cells. As a type 1 integral membrane glycoprotein, Env is cotranslationally translocated into the endoplasmic reticulum. In this report, we characterized the synthesis of Env, which did not occur at a constant rate but by translational/translocational pausing that has not previously been shown with a viral encoded glycoprotein. Overall translation was not impeded by the presence of the reducing agent dithiothreitol in vivo, although this did influence the cleavage of the precursor gp160 into its mature form, gp120. Env interacts transiently with resident components of the endoplasmic reticulum such as calnexin, which had maximal association at a 10-min post-translation. Addition of the glucosidase inhibitor, castanospermine, failed to significantly influence the association of Env with calnexin, consistent with the notion that calnexin recognizes components other than alpha-terminal glucose. Moreover, castanospermine treatment failed to affect the infectivity of virions. Taken together, this report demonstrates the existence of translational/translocational pausing for a viral glycoprotein and suggests that trimming of glucose from HIV-1 Env is not essential for the initiation of virus infection.
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PMID:Characterization of the biosynthesis of human immunodeficiency virus type 1 Env from infected T-cells and the effects of glucose trimming of Env on virion infectivity. 1105 27


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