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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Functional and structural studies were made to assess whether a class of antiviral agents targets the N-terminal domain of the glycoprotein 41,000 (gp41) of human immunodeficiency virus type 1 (HIV-1). Previous experiments have shown that the amino-terminal peptide (FP-I; 23 amino acids, residues 519-541) of HIV-1 gp41 is cytolytic to both human erythrocytes (non-CD4+ cells) and Hut-78 cells (CD4+ lymphocytes). Accordingly, FP-I-induced hemolysis may be used as a surrogate assay for evaluating the role of the N-terminal gp41 domain in HIV-cell interactions. Here, we studied the blocking of FP-I-induced lysis of erythrocytes by the following anti-HIV agents: (1) IgG [i.e., anti-(518-541) IgG] raised to an immunoconjugate of Arg-FP-I, (2) apolipoprotein A-1 (apo A-1) and a peptide based on apo A-1, (3) dextran sulfate, (4) gp41 peptide (residues 637-666), and (5) anionic human serum albumins. Dose-response curves indicated that their relative potency in inhibiting FP-I-induced hemolysis was approximately correlated with their previously reported anti-HIV activity. Electron spin resonance (ESR) studies showed that FP-I spin labeled at the N-terminal alanine binds to anti-(518-541) IgG, dextran sulfate, and anionic albumins. The high in vitro antiviral activity and low cytotoxicity of these agents suggest that blocking membrane-FP-I interactions offers a novel approach for AIDS therapy or prophylaxis.
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PMID:Antivirals that target the amino-terminal domain of HIV type 1 glycoprotein 41. 757 27

Cardiovascular disease (CVD) is the single most important cause of mortality in hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) patients. An increased lipoprotein (a) [Lp(a)] level in HD patients is associated with CVD. However, Lp(a) levels in CAPD patients are controversial, and their association with CVD has not been established. In the present study, prevalent CAPD and HD patients [excluding those who were human immunodeficiency virus (HIV)-positive] attending the Long Island College Hospital from June, 1990 to July, 1995 underwent analysis of lipid profile including Lp(a). Total and low-density lipoprotein cholesterol, triglycerides, apolipoprotein (apo) A, and apo B were all significantly increased in CAPD patients compared to HD patients. Serum Lp(a) levels were also significantly higher in CAPD patients than in HD patients (51 +/- 32 vs 34 +/- 23 mg/dL, p < 0.001). CAPD patients who had a history of myocardial infarction (MI) or coronary artery disease (CAD) at enrollment had significantly higher Lp(a) levels compared to those who did not have a history of MI or CAD. CAPD patients who died of CVD had higher Lp(a) levels than patients who died of non-CVD causes. In the Cox model with backward stepwise selection, a history of CVD was associated with a significantly elevated relative risk (RR) of mortality (RR = 1.84, p = 0.014). Expected survival by all causes of mortality and by cardiac mortality was significantly shorter in patients with a history of CVD than in those without a history of CVD. Thus, elevated Lp(a) is related to increased CVD and therefore may contribute to increased mortality in CAPD patients.
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PMID:Is an elevated level of serum lipoprotein (a) a risk factor for cardiovascular disease in CAPD patients? 886 17

In a previous work, we predicted and demonstrated that the 29-42-residue fragment of beta-amyloid peptide (Abeta peptide) has in vitro capacities close to those of the tilted fragment of viral fusion proteins. We further demonstrated that apolipoprotein E2 and E3 but not apolipoprotein E4 can decrease the fusogenic activity of Abeta(29-42) via a direct interaction. Therefore, we suggested that this fragment is implicated in the neurotoxicity of Abeta and in the protective effects of apolipoprotein E in Alzheimer's disease. Because structurally related apolipoproteins do not interact with the Abeta C-terminal domain but inhibit viral fusion, we suggested that interactions existing between fusogenic peptides and apolipoproteins are selective and responsible for the inhibition of fusion. In this study, we simulated interactions of all amphipathic helices of apolipoproteins E and A-I with Abeta and simian immunodeficiency virus (SIV) fusogenic fragments by molecular modeling. We further calculated cross-interactions that do not inhibit fusion in vitro. The results suggest that interactions of hydrophobic residues are the major event to inhibit the fusogenic capacities of Abeta(29-42) and SIV peptides. Selectivity of those interactions is due to the steric complementarity between bulky hydrophobic residues in the fusogenic fragments and hydrophobic residues in the apolipoprotein C-terminal amphipathic helices.
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PMID:Molecular determinants of the interaction between the C-terminal domain of Alzheimer's beta-amyloid peptide and apolipoprotein E alpha-helices. 1042 74

Several antiviral substances have been detected in human serum but few have been shown to possess broad antiviral activity. These broadly active antiviral molecules could be of significance as innate defense mechanisms. We have previously identified and characterized a broadly antiviral glycoprotein, UTI3, which accounts for 50 antiviral units/ml of human and mammalian sera. In addition there are reports of antiviral activity of human serum apolipoprotein A-1 (apo A-1), an important constituent of high density lipoprotein (HDL), against human immunodeficiency virus (HIV) and herpesvirus. Therefore we investigated (1) whether HDL is broadly antiviral, (2) how much of the broad antiviral activity of serum is due to HDL, and (3) the mechanism(s) of HDL's antiviral action. In this paper we report that (1) HDL does have broad antiviral activity, (2) HDL accounts for a modest but significant portion of the antiviral activity of serum, and (3) HDL acts by preventing virus penetration. Overall, HDL may be one of the broadly antiviral defences in the bloodstream.
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PMID:Lipoproteins account for part of the broad non-specific antiviral activity of human serum. 1044 33

Patients with human immunodeficiency virus show increased atheroembolism and premature arterial events (stroke, myocardial infarction), but no increased venous thromboembolism. This paper describes an association of elevated lipoprotein(a), a decreased prostaglandin I(2)(PGI(2)) synthesis stimulating plasma factor, diminished PGI(2)-stability in plasma and decreased high-density lipoprotein-cholesterol and apolipoprotein A. It is unclear to what extent these biochemical findings represent an acute phase reaction only or a disturbance in the prostaglandin system. Definitely, they are resulting in severe hemostatic imbalance decreasing local PGI(2)-availability with a dramatic reduction in the cytoprotective capacity favouring the onset of premature arterial events seen in some of the patients.
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PMID:Association of lipoprotein(a), prostaglandin I(2)--synthesis stimulating plasma factor, biological half-life of prostaglandin I(2)and high-density lipoproteins in HIV-1 infection of different stages. 1109 Feb 58

Neurological disorders develop in most people infected with human immunodeficiency virus type 1 (HIV-1). However, the underlying mechanisms remain largely unknown. Here we report that binding of HIV-1 transactivator (Tat) protein to low-density lipoprotein receptor-related protein (LRP) promoted efficient uptake of Tat into neurons. LRP-mediated uptake of Tat was followed by translocation to the neuronal nucleus. Furthermore, the binding of Tat to LRP resulted in substantial inhibition of neuronal binding, uptake and degradation of physiological ligands for LRP, including alpha2-macroglobulin, apolipoprotein E4, amyloid precursor protein and amyloid beta-protein. In a model of macaques infected with a chimeric strain of simian-human immunodeficiency virus, increased staining of amyloid precursor protein was associated with Tat expression in the brains of simian-human immunodeficiency virus-infected macaques with encephalitis. These results indicate that HIV-1 Tat may mediate HIV-1-induced neuropathology through a pathway involving disruption of the metabolic balance of LRP ligands and direct activation of neuronal genes.
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PMID:Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. 1110 Jan 24

Highly active antiretroviral therapy, which includes a combination of protease inhibitors, is highly successful in controlling human immunodeficiency virus (HIV) infection and reducing the morbidity and mortality of autoimmune deficiency syndrome (AIDS). However, the benefits of HIV protease inhibitors are compromised by numerous undesirable side effects. These include peripheral fat wasting and excessive central fat deposition (lipodystrophy), overt hyperlipidemia, and insulin resistance. The mechanism associated with protease inhibitor-induced metabolic abnormalities is multifactorial. One major effect of the protease inhibitor is its suppression of the breakdown of the nuclear form of sterol regulatory element binding proteins (nSREBP) in the liver and adipose tissues. Hepatic accumulation of nSREBP results in increased fatty acid and cholesterol biosynthesis, whereas nSREBP accumulation in adipose tissue causes lipodystrophy, reduces leptin expression, and promotes insulin resistance. The HIV protease inhibitors also suppress proteasome-mediated breakdown of nascent apolipoprotein (apo) B, thus resulting in the overproduction and secretion of triglyceride-rich lipoproteins. Finally, protease inhibitor also suppresses the inhibition of the glucose transporter GLUT-4 activity in adipose and muscle. This latter effect also contributes directly to insulin resistance and diabetes. These adverse effects need to be alleviated for long-term use of protease inhibitor therapy in treatment of HIV infection.
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PMID:Effects of HIV protease inhibitor therapy on lipid metabolism. 1254 52

There is accumulating evidence that human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) can induce hyperlipidaemia. To evaluate the frequency and type of hyperlipidaemia in PI-treated patients, 98 outpatients were prospectively analysed for their lipoprotein characteristics at the Medizinische Hochschule in Hannover, Germany. Fifty-seven percent of the patients studied presented with hyperlipidaemia. Both hypertrigylceridaemia (type IV and V hyperlipoproteinaemia, 33%) and hypercholesterolaemia (type IIa hyperlipoproteinaemia, 6%) were detectable. The remaining 18% had a type IIb hyperlipoproteinaemia. Increased lipid levels were highly statistically significant compared to a control group of PI-naive HIV-1-infected patients [low-density lipoprotein (LDL) 146 mg/dl (range, 53-274 mg/dl) versus 105 mg/dl (range, 22-188 mg/dl; P=0.0006); very-low-density lipoprotein (VLDL) 35.5 mg/dl (5-253 mg/dl) versus 18 mg/dl (range, 3-94 mg/dl; P=0.0002)]. All PIs used (saquinavir, indinavir, nelfinavir and ritonavir) were associated with this variable form of hyperlipidaemia according to the Fredrickson classification. There was no significant correlation of any determined lipid value with the duration of treatment. A higher frequency of the apolipoprotein E2 allele and E4 allele was observed in the hyperlipidaemic subjects. Patients with excessive hypertriglyceridaemia showed a reduced lipoprotein lipase activity. Lipodystrophy was observed especially in hyperlipidaemic patients and to a lesser extent in normolipidaemic subjects. The frequency of hyperlipidaemic risk factors was surprisingly high in the group studied, which in turn may explain the proposed increased risk of atherogenesis in HIV-1 PI-treated patients. Therefore, PI-treated subjects should also be evaluated for their lipoprotein pattern, which may require antihyperlipidaemic interventions.
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PMID:Lipid evaluation in HIV-1-positive patients treated with protease inhibitors. 1273 56

Many circumstances can induce activation and/or injury of the endothelium that plays a role in the development of vascular complications. Raised plasma levels of endothelial markers such as von Willebrand factor (vWF), soluble thrombomodulin (sTM) and soluble vascular cell adhesion molecule-1 (sVCAM-1) have a prognostic and/or diagnostic value. Human immunodeficiency virus-infected patients (HIV+) have a clustering of conditions that activate or injure the endothelium. Highly active antiretroviral treatment produces adverse effects such as dyslipemia, insulin resistance (IR) and body fat changes (named lipodystrophy syndrome) which may contribute to aggravate their endothelial perturbation. The aim of this study was to measure lipid profile, insulin resistance status, and endothelial markers in 38 HIV+ naive of antiretroviral treatment and 63 HIV+ under highly active antiretroviral treatment (33 with lipodystrophy syndrome and 30 without it). Body fat distribution was also evaluated by dual-energy X-ray absorptiometry (DEXA) analysis. Thirty-one HIV negative subjects were used as controls. We looked for association between variables. Insulin resistance status was a common finding in the four groups. Lipodystrophic patients presented an atherothrombotic lipid profile [elevated levels of triglycerides (TG), low-density lipoprotein cholesterol (LDL-chol) and apolipoprotein-B (APO-B)] and a strong loss of fat in legs and arms (lipoatrophy). All endothelial markers evaluated in our naive patients were higher as compared to control group. sVCAM-1 in HIV+ under therapy without lipodystrophy syndrome showed significantly decreased levels as compared to naive group (487 vs. 666 ng/ml) and vWF and sTM tended to diminish although they did not show a significant difference (130% vs. 170%, 41 vs. 45 ng/ml, respectively). Lipodystrophic patients showed a tendency to increased levels of endothelial activation markers (sVCAM-1: 500 ng/ml and vWF: 154%) together with significantly increased levels of an endothelial injury marker (sTM: 50 ng/ml) with respect to HIV+ under therapy without lipodystrophy syndrome. Plasma levels of sTM, as an endothelial injury marker, correlated with peripheral lipoatrophy (rho = -0.357) in lipodystrophic patients. In conclusion, despite the beneficial immunology effect of highly active antiretroviral treatment and the apparent decrease in the endothelial perturbation, the patients who develop lipodystrophy present altered endothelial markers and other risk factors, such as IR and dyslipemia, which turn them into a high atherothrombotic risk group.
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PMID:Endothelial markers and HIV infection in the era of highly active antiretroviral treatment. 1289 23

Human immunodeficiency virus (HIV) is rapidly becoming a global health concern. Proteomics technology was employed to examine HIV infected plasma samples in an attempt to identify disease-associated proteins. By comparison with normal and HIV positive plasma samples, at least eight proteins were significantly changed in HIV infected plasma. In particular, apolipoprotein AI presents a heterogeneous change in expression level with different isoforms. Apolipoprotein AI could be a useful biomarker for HIV diagnosis.
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PMID:Different isoforms of apolipoprotein AI present heterologous post-translational expression in HIV infected patients. 1720 62


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