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)

The methylation and transsulfuration pathways are intimately linked and have been implicated in the progression of neurologic damage and immune cell depletion caused by human immunodeficiency virus (HIV) infection. We studied the following metabolites related to these pathways: S-adenosylmethionine (SAMe), homocysteine, cysteine, cysteinyl-glycine, and glutathione (GSH) in blood and CSF of 16 HIV-infected patients with neurologic complications and 20 HIV-negative control patients undergoing lumbar punctures for other medical reasons. We confirmed recent studies of decreased CSF SAMe concentrations in HIV infection and demonstrated that diastereomers of SAMe are present in CSF but not in plasma or erythrocytes from both HIV-infected and HIV-negative patients. In HIV-infected patients, CSF GSH and cysteinyl-glycine, but not homocysteine or cysteine, were significantly reduced. This is the first report of decreased CSF GSH induced by HIV infection. GSH has a regulatory effect on the synthesis of SAMe in hepatic tissue, and the same mechanism may also apply in the CNS. Administration of SAMe-butanedisulphonate, 800 mg/d intravenously for 14 days, was associated with significant increases in CSF SAMe and GSH. These findings have potentially important therapeutic implications for the use of SAMe in protecting against SAMe and GSH deficiency in the CNS of HIV-infected patients.
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PMID:Cerebrospinal fluid S-adenosylmethionine (SAMe) and glutathione concentrations in HIV infection: effect of parenteral treatment with SAMe. 767 26

Asymptomatic human immunodeficiency virus (HIV)-seropositive individuals have reduced glutathione (GSH) levels. This has led to the suggestion that elevated intracellular thiols levels may inhibit HIV replication and progression of the disease. We confirmed that N-acetyl-L-cysteine (NAC), a cysteine prodrug which maintains intracellular GSH levels during oxidative stress, inhibits in the chronically infected U1 cells, the stimulation of HIV replication induced by phorbol 12-myristate 13-acetate (PMA), interleukin-6 (IL-6) or granulocyte-macrophage colony stimulating factor (GM-CSF). However, we found no significant inhibition of PMA-mediated long terminal repeat (LTR)-directed beta-galactosidase expression in transiently transfected Jurkat T-cells. We have compared NAC effects with the effects of other GSH precursors on HIV expression. Treatment of the U1 cell line by L-2-oxo-4-thiazolidine carboxylic acid (OTC), which is converted to cysteine by 5-oxoprolinase, or by homocysteine (HC), a natural cysteine precursor, reduced the PMA-induced HIV expression, but surprisingly, markedly stimulated the expression mediated by IL-6 and GM-CSF. Several experiments to investigate the effect of OTC on LTR transactivation were carried out, but beta-galactosidase activity was never modified in a significant fashion in PMA-induced Jurkat T-cells after OTC treatment. Furthermore, HC stimulated the PMA-mediated HIV-LTR transactivation in Jurkat T-cells. GSH assays showed that treatment of U937 and Jurkat T-cells with NAC and OTC moderately increased the GSH level, while HC led to a significantly higher increase of the thiol level. In conclusion, it appeared that an increase of the GSH intracellular level did not lead solely to an inhibition of HIV replication but could also lead to an activation of viral expression. This seemed the case when HIV replication was stimulated by compounds which act mainly at a post-transcriptional level.
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PMID:Effects of glutathione precursors on human immunodeficiency virus replication. 819 36

Oxidative stress has been suggested to be an important factor in the immunopathogenesis of human immunodeficiency virus (HIV) infection. Reduced plasma thiols may lead to production of reactive oxygen species, thus contributing to the oxidative stress. We quantified the total, reduced, and protein-bound forms of the thiols homocysteine, cysteine, cysteinylglycine, and methionine in plasma from 21 HIV-infected patients and 15 healthy control subjects and compared the results with clinical and immunologic indexes. The HIV-infected patients had significantly higher concentrations of reduced homocysteine in plasma compared with control subjects. No significant differences in reduced homocysteine concentrations were noted when asymptomatic and symptomatic HIV-infected patients were compared, and we did not find any relation between reduced homocysteine concentrations and other markers of immunodeficiency. The HIV-infected patients had normal total homocysteine concentrations. The reduced cysteinylglycine concentration tended to be elevated in the patient group. No differences between HIV-infected patients and control subjects were found for reduced or total cysteine. Compared with control subjects, the HIV-infected patients had lower concentrations of methionine in plasma, and a significant correlation was found between low concentrations of methionine and low CD4+ lymphocyte counts in blood. Elevated concentrations of reduced homocysteine could possibly contribute to formation of reactive oxygen species, leading to accelerated immunologic deterioration and increased HIV replication.
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PMID:Elevated plasma concentration of reduced homocysteine in patients with human immunodeficiency virus infection. 856 Oct 66

Based on previous studies from our group, we hypothesized that enhanced oxidative stress in association with a persistent immune activation may be important in both the immunopathogenesis and certain clinical manifestations in a subgroup of patients with common variable immunodeficiency (CVI). To explore this hypothesis further, we examined plasma levels of lipid peroxidation, antioxidant vitamins and redox status of various thiol species in 20 CVI patients and 16 healthy control subjects. We found significantly higher malondialdehyde (MDA) levels in plasma from CVI patients than in healthy control subjects. Furthermore, in a subgroup of CVI patients characterized by persistent immune activation in vivo (CVIHyper), we found significantly decreased levels of vitamin E and beta-carotene. In the CVI patients, there was a significant inverse correlation between MDA levels and levels of vitamin E and beta-carotene. Finally, we found a marked elevation in plasma levels of reduced homocysteine in the CVI group, but no corresponding rise in plasma levels of total homocysteine. In the CVI group, the high plasma levels of reduced homocysteine were significantly correlated with enhanced lipid peroxidation and low levels of vitamin E. The results of the present study further support a role for enhanced oxidative stress in the immunopathogenesis of CVI. Furthermore, our finding of markedly elevated plasma levels of reduced homocysteine in CVI patients without simultaneous elevation of other homocysteine species suggests that this disturbance in homocysteine metabolism may be related to enhanced oxidative stress.
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PMID:Elevated plasma levels of reduced homocysteine in common variable immunodeficiency--a marker of enhanced oxidative stress. 935 42

Serum vitamin B12 levels are often low in human immunodeficiency virus (HIV)-infected patients. However, only a few patients appear to have actual vitamin B12 deficiency. A low red cell folate level accompanying the low vitamin B12 level makes the presence of vitamin B12 deficiency more likely. Our experience suggests that a low red cell folate level always indicates deficiency, but does not differentiate between vitamin B12 and folate deficiency. The deoxyuridine suppression test and the assay of serum or plasma total homocysteine and/or of methylmalonic acid levels can also be useful in the identification of patients with true vitamin B12 deficiency. HIV-positive patients frequently have absorption disorders, including vitamin B12 malabsorption. However, the correlation between vitamin B12 malabsorption and serum vitamin B12 and plasma homocysteine levels is poor. Abnormalities in vitamin B12-binding proteins, which are often found in HIV-positive patients, may explain many cases of low vitamin B12 levels. Current evidence suggests that low vitamin B12 levels are more common as the HIV disease progresses. The results of vitamin B12 treatment have been disappointing thus far, including the prevention of toxicity induced by azidothymidine. The possible role of vitamin B12 treatment in the long-term survival of HIV-infected patients is at present unknown. However, it is important to identify those patients who have real vitamin B12 deficiency to treat or prevent their hematologic and/or neurological symptoms.
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PMID:Cobalamin deficiency in patients infected with the human immunodeficiency virus. 993 May 70

This study investigates fasting serum levels of methionine and related metabolites, vitamin B6, and folate during highly active antiretroviral therapy in therapy-naive human immunodeficiency virus (HIV)-1-infected outpatients. The research design consisted of before and during therapy measurements with a median treatment period of 100 days (range, 50 to 188) in frozen samples. The subjects included 17 consecutive HIV-1-infected outpatients (15 men and 2 women; 25 to 65-years-old). Controls were 42 healthy individuals (28 men and 14 women; 24- to 82-years-old) without serologic evidence of HIV and/or hepatitis C infection and normal clinical chemistry. Subjects received treatment with the reverse transcriptase inhibitors, azidothymidine (AZT) or stavudine (D4T) plus lamivudine (3TC) and either the protease inhibitors, indinavir (IND), nelfinavir (NELF), ritonavir (RITV), or saquinavir (SAQ) at the standard dosage. Serum concentrations of methionine, total homocysteine (tHcy), cystathionine (CYSTA), N,N-dimethylglycine (DMG), N-methylglycine (MG), methylmalonic acid (MMA), and total cysteine, as well as vitamin B6, folate, and soluble tumor necrosis factor receptor p75 were taken at baseline and during highly active antiretroviral therapy. Baseline, serum tHcy, MMA, CYSTA, vitamin B6 concentrations were not significantly different from healthy controls. There was, however, a trend towards lower folate serum concentrations at baseline in HIV-infected patients as compared with healthy controls (P =.06). There were no significant correlations between tHcy and vitamin B6, folate, or MMA. Elevated baseline levels of DMG and MG decreased significantly during antiretroviral therapy (P =.0019 and.04, respectively), whereas no significant changes in serum concentrations of CYSTA, MMA, or methionine were detected. tHcy increased in 12 of 17 patients (P =.09). HIV-infected patients displayed significant alterations (elevated DMG and MG serum concentrations) in metabolite levels of the betaine pathway in methionine metabolism, which might be positively influenced by newly initiated antiretroviral combination therapy.
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PMID:Decrease of elevated N,N-dimethylglycine and N-methylglycine in human immunodeficiency virus infection during short-term highly active antiretroviral therapy. 1169 44

The high global prevalence of human immunodeficiency virus (HIV) infection has been associated with high morbidity and mortality. The advent of highly active antiretroviral therapy (HAART) has, however, dramatically increased survival of patients infected with HIV. These patients now survive to develop metabolic complications of HIV infection and its treatment, including increased predisposition to atherosclerotic disease. HIV infection is normally associated with hypocholesterolaemia, hypertriglyceridaemia, low plasma HDL-cholesterol as well as alterations in other cardiovascular risk factors including inflammatory markers, clotting factors, homocysteine, apolipoproteins, lipoprotein (a), oxidative stress and non-esterified fatty acids. The use of HAART is, in particular, associated with dyslipidaemia and lipodystrophy with underlying insulin resistance and associated glucose intolerance. This article explores the metabolic abnormalities associated with increased cardiovascular risk that occur in HIV infection before and after antiretroviral therapy. The laboratory investigation and clinical management of HIV-associated dyslipidaemia and lipodystrophy will be discussed.
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PMID:The basis and management of metabolic abnormalities associated with cardiovascular risk in human immunodeficiency virus infection and its treatment. 1745 92

A 20-year-old man was hospitalized for malignant hypertension, mechanical hemolysis, and kidney failure. Kidney biopsy confirmed glomerular and arteriolar thrombotic microangiopathy. Etiologic analyses, which included ADAMTS13 activity, stool culture, complement factor proteins (C3, C4, factor H, factor I, and MCP [membrane cofactor protein]), anti-factor H antibodies, HIV (human immunodeficiency virus) serology, and antinuclear and antiphospholipid antibodies, returned normal results. Malignant hypertension was diagnosed. Ten months later, we observed a relapse of acute kidney injury and mechanical hemolysis. Considering a diagnosis of complement dysregulation-related atypical hemolytic uremic syndrome (HUS), we began treatment with eculizumab. Despite the efficient complement blockade, the patient's kidney function continued to decline. We performed additional analyses and found that the patient's homocysteine levels were dramatically increased, with no vitamin B12 (cobalamin) or folate deficiencies. We observed very low plasma methionine levels associated with methylmalonic aciduria, which suggested cobalamin C disease. We stopped the eculizumab infusions and initiated specific treatment, which resulted in complete cessation of hemolysis. MMACHC (methylmalonic aciduria and homocystinuria type C protein) sequencing revealed compound heterozygosity for 2 causative mutations. To our knowledge, this is the first report of adult-onset cobalamin C-related HUS. Considering the wide availability and low cost of the homocysteine assay, we suggest that it be included in the diagnostic algorithm for adult patients who present with HUS.
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PMID:Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency. 2421 May 89

Introduction Human immunodeficiency virus (HIV) patients are at risk of developing thrombosis than general population. There are several intersecting mechanisms associated with HIV infection and antiviral therapy that are emerging, which may lead to vasculopathy and hypercoagulability in these patients. Methods We analyzed the HIV patients who followed up with our Vascular Medicine outpatient clinic with venous thromboembolism (VTE) over the past 3 years and followed them prospectively. The patients included were those who had minimum, regular follow-up of 3 months, with a Doppler scan in the beginning and last follow-up. Patients were analyzed for age, gender, race, site of thrombosis, coagulation factors, lipid panel, type of antiretroviral treatment, past or present history of infections or malignancy, CD4 absolute and helper cell counts at the beginning of thrombosis, response to treatment and outcome. Patients with HIV with arterial thrombosis were excluded. Results A total of eight patients were analyzed. The mean age was 49.87 years (range, 38-58 years). All were male patients with six patients having lower limb thrombosis, one patient with upper limb thrombosis related to peripheral inserted central catheter (PICC), and one patient had pulmonary embolism with no deep vein thrombosis. Most common venous thrombosis was popliteal vein thrombosis, followed by common femoral, superficial femoral and external iliac thrombosis. Two patients had deficiency of protein S, two had high homocysteine levels, one had deficiency of antithrombin 3, and one had increase in anticardiolipin Immunoglobulin antibody. All patients were taking nucleoside and nonnucleoside inhibitors but only two patients were taking protease inhibitors. There was history of lymphoma in one and nonsmall cell lung carcinoma in one patient. Three patients had past history of tuberculosis and one of these patients also had pneumocystis carinii pneumonia. The mean absolute CD4 counts were 383.25 cells/UL (range, 103-908 cells/UL) and helper CD4 counts were 22.5 cells/UL (range, 12-45 cells/UL). All were anticoagulated with warfarin or enoxaparin. There was complete resolution of deep vein thrombosis in two patients (one with PICC line thrombosis in 3 months and other with popliteal vein thrombosis in 1 year). There was extension of clot in one patient and no resolution in others. Seven patients are still alive and on regular follow-up. Conclusion Thrombosis in HIV patients is seen more commonly in middle aged, community ambulant male patients. Left lower limb involvement with involvement of popliteal vein is most common. Deficiency of protein S and hyperhomocystenaemia were noted in these patients. Most of these patients did not respond to therapeutic anticoagulation, but the extension of the thrombosis was prevented in majority of cases.
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PMID:Risk of Venous Thromboembolism in Patients Infected with HIV: A Cohort Study. 2443 91

Patients with human immunodeficiency virus (HIV) are at risk of developing thrombosis and are 8 to 10 times more likely to develop thrombosis than the general population. Moreover, if they have hypercoagulable state they can have severe thrombosis and life-threatening thrombotic events. The purpose of this retrospective study is to analyze hypercoagulable state in HIV-seropositive patients who have been diagnosed with venous thromboembolism (VTE). This study is a subgroup study of a larger cohort group of HIV-seropositive patients with VTE followed up with our vascular medicine outpatient clinic. The patients included for this study were HIV-seropositive patients with hypercoagulable state, analyzed over the past 3 years, and followed prospectively. HIV-seropositive patients with arterial thrombosis were excluded. These patients had minimum, regular follow-up of 3 months, with a Doppler scan in the beginning and last follow-up. All the patients were analyzed for hypercoagulable state and the patients selected in this study were those who were tested positive for hypercoagulable state. All patients were analyzed for age, gender, race, site of thrombosis, coagulation factors, lipid panel, type of antiretroviral treatment, past or present history of infections or malignancy, CD4 absolute and helper cell counts at the beginning of thrombosis, and response to treatment and outcome. Patients with HIV with arterial thrombosis were excluded. The study was approved by the ethics committee. Five patients were included in this study. The mean age was 47.8 years (range 38 to 58 years). All were male patients with lower limb thrombosis. Most common venous thrombosis was popliteal vein thrombosis, followed by common femoral, superficial femoral, and external iliac thrombosis. Two patients had deficiency of protein S, two had high homocysteine levels, one had deficiency of antithrombin 3, and one had increase in anticardiolipin immunoglobulin G antibody. All the patients were taking nucleoside and nonnucleoside inhibitors but only one patient was taking protease inhibitors. There was no history of malignancy but two patients had past history of tuberculosis. The mean absolute CD4 counts were 244 cells/UL (range 103 to 392 cells/UL) and helper CD4 counts were 19.6 cells/UL (range 15 to 30 cells/UL). All were anticoagulated with warfarin or enoxaparin. There was complete resolution of deep vein thrombosis only in one patient on long-term anticoagulation but there was no resolution of thrombosis in the other four patients despite of therapeutic anticoagulation for more than 6 months. All the patients are alive and on regular follow-up. Thrombosis in HIV patients is seen more commonly in middle aged, community ambulant male patients. The most common hypercoagulable state was noted as deficiency of protein S and hyperhomocysteinemia. Eighty percent of the patients did not respond to therapeutic anticoagulation.
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PMID:A Case Series of HIV-Seropositive Patients and Hypercoagulable State-Is It Difficult to Treat Even with Therapeutic Anticoagulation? 2443 93


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