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

Human immunodeficiency virus type 1 (HIV-1) seropositive individuals suffer from a depletion of T4+ T cells and have elevated plasma glutamate levels. Glutamate is also elevated in cancer patients, and several authors have shown that elevated extracellular glutamate levels inhibit competitively the membrane transport of cystine and cause a decrease of intracellular cystine. We, therefore, tested the hypothesis that high glutamate and/or low cystine levels may generally be associated with low lymphocyte reactivity or low T4+ counts. In three independent studies we tested (i) serum amino acid levels (AAL) versus T4+ counts in healthy individuals, (ii) plasma AAL versus lymphocyte responses in healthy individuals, and (iii) plasma AAL versus T4+ counts in HIV-1 seropositive individuals. When the individuals in each study were divided into four subgroups as defined by median glutamate and cystine levels, the results showed that persons with a combination of low glutamate and high cystine level (LGHC subgroups) had the highest mean T4+ count or highest lymphocyte reactivity. Moreover, the LGHC subgroup in a study of lung cancer patients had a much longer mean survival time than the other three subgroups. In HIV-1 infected patients, hyperglutamataemia is associated with hypocystinaemia and hypocysteinaemia. Azidodeoxythymidine (AZT) treated HIV patients had, on average, lower glutamate levels than patients without AZT.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:T4+ cell numbers are correlated with plasma glutamate and cystine levels: association of hyperglutamataemia with immunodeficiency in diseases with different aetiologies. 134 32

When the plasma glutathione concentration is low, such as in patients with HIV infection, alcoholics, and patients with cirrhosis, increasing the availability of circulating glutathione by oral administration might be of therapeutic benefit. To assess the feasibility of supplementing oral glutathione we have determined the systemic availability of glutathione in 7 healthy volunteers. The basal concentrations of glutathione, cysteine, and glutamate in plasma were 6.2, 8.3, and 54 mumol.l-1 respectively. During the 270 min after the administration of glutathione in a dose of 0.15 mmol.kg-1 the concentrations of glutathione, cysteine, and glutamate in plasma did not increase significantly, suggesting that the systemic availability of glutathione is negligible in man. Because of hydrolysis of glutathione by intestinal and hepatic gamma-glutamyltransferase, dietary glutathione is not a major determinant of circulating glutathione, and it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione.
 ...
PMID:The systemic availability of oral glutathione. 136 56

Markedly decreased plasma cystine and cysteine concentrations have been found in HIV-infected patients at all stages of the disease and in SIV-infected rhesus macaques. The elevated glutamate levels found in the same patients aggravate the cysteine deficiency by inhibiting the membrane transport activity for cystine. The intact immune system appears to require a delicate balance between pro-oxidant and antioxidant conditions, maintained by a limited and well-regulated supply of cysteine. This balance is obviously disturbed in HIV infection and may contribute to the pathogenesis of AIDS.
 ...
PMID:HIV-induced cysteine deficiency and T-cell dysfunction--a rationale for treatment with N-acetylcysteine. 137 79

The central nervous system manifestations of AIDS were originally thought to consist solely of white matter lesions, but recent evidence has shown that a substantial degree of neuronal loss can also occur. This review presents evidence for HIV-related toxic factors that may account at least in part for this newly-recognized neuronal injury. One potential neurotoxin is the HIV-1 envelope glycoprotein gp-120 or a fragment of this molecule. This coat protein is shed by the virus and potentially released from HIV-infected immune cells. In tissue culture experiments on rodent neurons, gp120 produces an early rise in intracellular calcium concentration and, subsequently, delayed-onset neurotoxicity. In addition, HIV-infected macrophages or microglia release as yet undefined toxic factor(s) that kill rodent, chick, and human neurons in vitro. It is as yet unknown if one of these macrophage toxic factors might represent a gp120 fragment, or alternatively, if gp120, in the absence of HIV-1 infection, might be capable of activating macrophages to release these toxic factor(s). In at least some neuronal cell types, gp120-induced neurotoxicity can be prevented by antagonists of L-type voltage-dependent calcium channels or by antagonists of N-methyl-D-aspartate (NMDA, a subtype of glutamate receptor). Degradation of endogenous glutamate also protects neurons from gp120-related neuronal injury, suggesting that gp120 and glutamate are both necessary for neuronal cell death as synergistic effectors. Antagonists acting at the other types of glutamate receptors (non-NMDA antagonists) are ineffective in affording protection from gp120.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:HIV-related neurotoxicity. 166 8

Exposure of rat retinal cultures to HIV-1 coat protein gp120 for several minutes increases [Ca2+]i in approximately half of the ganglion cells; this effect is associated with delayed-onset neuronal injury, similar to that previously reported in NMDA receptor-mediated neurotoxicity. Here we show that NMDA antagonists can prevent both the rise in [Ca2+]i and subsequent neuronal damage engendered by 20 pM gp120. However, whole-cell patch-clamp recordings demonstrate that gp120 does not directly evoke an NMDA-like response or enhance glutamate/NMDA-activated currents. Moreover, complete protection from gp120-induced [Ca2+]i increases and neurotoxicity is afforded by incubation with glutamate-pyruvate transaminase, which breaks down endogenous glutamate as verified by HPLC. Since, under standard conditions in these cultures, neither glutamate nor a low picomolar concentration of gp120 is deleterious on its own, our results suggest that their neurotoxicity is synergistic.
 ...
PMID:Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity. 167 93

To establish whether the high plasma glutamate and low acid-soluble thiol (mainly cysteine) concentrations previously found in patients with HIV-1 infection are a consequence of the infection or a risk factor for its development, a closely related animal model, rhesus and fascicularis macaques infected with simian immunodeficiency virus (SIVmac251), was studied. The 23 infected macaques had significantly lower mean plasma thiol and higher glutamate concentrations than 18 uninfected controls (p less than 0.001). The changes were apparent by 1 week after infection. Thus, abnormal plasma glutamate and thiol concentrations are, at least in this model, a direct and early consequence of the retroviral infection.
 ...
PMID:Metabolic disorder as early consequence of simian immunodeficiency virus infection in rhesus macaques. 168 16

Two conserved sequence motifs, occurring in HIV-1 reverse transcriptase at residues 110-116 and 183-190, have been studied using site-directed mutagenesis of the cloned gene. In particular, aspartates at positions 185 and 186 have each been mutated to either asparagine or glutamate. The resulting mutant proteins were catalytically inactive but still able to bind the template-primer complex, poly rA-oligo dT. Other mutations in these regions resulted in reduced reverse trascriptase activity but the mutation of tyrosine-183 to serine caused a significant increase in the Km for dTTP and the Ki for inhibition by 3'-azidothymidine-triphosphate, 2',3'-dideoxythymidine-triphosphate and phosphonoformic acid.
 ...
PMID:Mutational analysis of two conserved sequence motifs in HIV-1 reverse transcriptase. 170 76

The discovery of decreased plasma cysteine and cystine levels and elevated plasma glutamate levels in HIV-infected patients has led to intense investigations into the role of cysteine in T cell-mediated immune responses. A large body of evidence indicates that certain aspects of the T cell response require the action of active oxygen derivatives while other aspects of the response require the action of antioxidants such as cysteine and glutathione (GSH). The prooxidant and antioxidant states may be required sequentially at different times during T cell activation. The extremely weak cystine transport activity of T cells together with oxidizing metabolites from inflammatory microenvironments appear to be important factors that support the prooxidant state. The relatively high cystine transport activity of the antigen-presenting macrophages, in contrast, provides these cells with a "cysteine pumping" function that allows the antigen binding T cells in their vicinity to shift to the antioxidant state. The difference between the membrane transport activities for cysteine of T cells and macrophages thus appears to be the key element of a mechanism that facilitates both, the prooxidant state of T cells and their regulated shift to the antioxidant state. When T cells do not receive sufficient amounts of cysteine, the intracellular GSH levels and rates of DNA synthesis activity decrease, and the cells may suffer from various manifestations of oxidative damage.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Requirement for prooxidant and antioxidant states in T cell mediated immune responses.--Relevance for the pathogenetic mechanisms of AIDS? 179 89

Human immunodeficiency virus infection is frequently complicated by a syndrome of central nervous system dysfunction known as the acquired immunodeficiency syndrome dementia complex (ADC). The ADC is characterized by abnormalities in cognition, motor performance, and behavior, and it produces serious morbidity in a significant number of patients with acquired immunodeficiency syndrome. The pathogenesis of ADC is unclear, but appears to be caused by the human immunodeficiency virus itself, rather than by a secondary opportunistic process. Herein, we review the data regarding the pathogenesis of ADC and hypothesize a mechanism involving excitotoxicity and dopaminergic dysfunction. N-methyl-D-aspartate receptor antagonists may be of therapeutic benefit, as these agents may both limit glutamate-mediated neuronal dysfunction and improve dopaminergic neuronal function.
 ...
PMID:Excitotoxicity and dopaminergic dysfunction in the acquired immunodeficiency syndrome dementia complex. Therapeutic implications. 184 34

The subsite requirements of the aspartic proteinase from the myeloblastosis-associated virus (MAV) for the cleavage of peptide substrates were studied with a series of synthetic peptides of general structure Ala-Thr-P4-P3-P2-P1*Nph-Val-Arg-Lys-Ala. The residues in positions P4, P3, P2 and P1 were varied and the kinetic parameters for the cleavage of substrates in 2.0 M NaCl were spectrophotometrically determined at pH 6.0 and 37 degrees C. The acceptance of amino acid residues in particular subsites is similar to that observed with the human immunodeficiency virus type 1 (HIV-1) proteinase in our earlier studies on the same substrate series: hydrophobic or aromatic residues are preferable in P1 position, a broad variety of residues are acceptable in P3 whereas the residues occupying P2 plays the decisive role in the substrate cleavage as evidenced by its dramatic influence on both kcat and Km values. The most remarkable difference between the two enzymes was found in P3 and P4 subsites. In P3, the introduction of negatively charged glutamate increases the substrate binding by the MAV proteinase 12-fold and decreases binding by the HIV-1 proteinase. In P4, Pro in this series is a favourable residue for the MAV proteinase and is strongly inacceptable for HIV-1 the proteinase. The pH profile of the cleavage was studied with a chromogenic substrate and differences between HIV-1 and MAV proteinases are discussed.
 ...
PMID:Subsite specificity of the proteinase from myeloblastosis associated virus. 202 69


1 2 3 4 5 6 7 8 9 10 Next >>