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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuronal loss observed in AIDS patients may be partly due to the neurotoxicity of HIV coat protein gp120, whose mechanism of action has been suggested to involve an interaction with voltage-dependent Ca2+ channels and NMDA receptors (Lipton, Trends Neurosci 15:75-79, 1992). In the present investigation we analyzed the acute neurotoxicity of gp120 on a purified neuronal population (rat cerebellar granule cell cultures) amply used for studies on glutamate toxicity. Cultures of 7-8 days were exposed for 15 min to a buffered Locke's solution containing the substances under study, washed, and cultured for another 24 hr in their original medium. The cells were stained with the nuclear dyes propidium iodide (for dead cells) and Hoechst 33258 (for total cells) and counted. Average cell death in controls was 8%. gp120 (1 pM-10 nM) caused an increase of cell death of about 80%. The effect was totally antagonized by NMDA antagonists (1 mM APV and 10 microM MK-801), by 1 microM nifedipine, and by anti-gp120 antibodies. At a concentration of 100 microM glutamate caused an average 130% increase of cell death, which was totally antagonized by APV. The effect of gp120 or glutamate did not appear to be mediated by the secretion of neurotoxins by nonneuronal cells present in a low proportion in the cultures nor to be due to the inactivation of (or competition with) neurotrophic factors present in the medium. The simultaneous administration of gp120 and glutamate (in various combinations of concentrations) had an effect that was less than additive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurotoxicity of HIV coat protein gp120, NMDA receptors, and protein kinase C: a study with rat cerebellar granule cell cultures. 768 Nov 15

A substantial number of adults and half of the children with acquired immunodeficiency syndrome (AIDS) suffer from neurological manifestations. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss, although neurons themselves do not appear to be infected by HIV-1. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells, especially after interacting with astrocytes, secrete neurotoxic substances. Not all of these substances are yet known, but they may include eicosanoids, platelet-activating factor, quinolinate, cysteine, cytokines, and free radicals. Macrophages activated by HIV-1 envelope protein gp120 also appear to release similar toxins. Some of these factors can lead to increased glutamate release or decreased glutamate reuptake. A final common pathway for neuronal suceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-asparate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:Neuronal injury associated with HIV-1 and potential treatment with calcium-channel and NMDA antagonists. 770 21

A recombinant vaccinia virus was used to express a mutation in the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120-gp41. In this mutant protein, the second amino acid in the N-terminal region of gp41 has been converted from a hydrophobic valine residue to the polar glutamate. When recombinant vaccinia viruses encoding wild-type HIV-1 envelope glycoprotein infect a lymphocyte cell line lacking CD4, the cells express the HIV-1 envelope glycoprotein gp120-gp41 and are able to fuse with a CD4(4) T lymphocyte cell line. Cells expressing the mutant envelope glycoprotein are unable to fuse with CD4(4) T lymphocytes. When both viruses infect CD4- cells simultaneously, there is an inhibition of fusion to CD4+ cells with an increasing fraction of the virus encoding the mutated envelope glycoprotein. Interestingly, when the opposing, or CD4+ target cells are infected with the mutation-expressing virus, while CD4- cells are infected with wild-type envelope-expressing virus, a similar inhibition of fusion is observed. This suggests that the mutated envelope glycoprotein does not need to reside in the same membrane as the wild-type protein it inhibits.
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PMID:A trans-dominant mutation in human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41 inhibits membrane fusion when expressed in target cells. 774 81

Glutamate release from rat and mouse microglia subcultures grown in a serum-free medium was substantially greater in the presence than in the absence of a physiological concentration of glutamine (0.5 mM). Mouse microglia produced and released more glutamate than rat microglia. Glutamate accumulation in the medium increased with time and cell density, which is consistent with the virtual absence of glutamate reuptake. Lipopolysaccharide (LPS; 10-100 ng/ml), HIV coat protein gp120 (0.1-10 nM), high K+ (35 mM) or ATP (150 microM), did not affect glutamate release from cells maintained in serum-free medium. In the presence of 1% dialyzed serum, however, LPS induced a dose- and time-dependent increase in the accumulation of glutamate in the medium, suggesting that, as in other cell types, serum factors are required for LPS binding to its receptors.
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PMID:Glutamate production by cultured microglia: differences between rat and mouse, enhancement by lipopolysaccharide and lack effect of HIV coat protein gp120 and depolarizing agents. 782 92

Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:AIDS-related dementia and calcium homeostasis. 784 72

Neurological complications observed in HIV-infected patients are very frequent. Neocortical lesions include reduced neuronal density due to neuronal degeneration. The HIV envelope protein gp120 has potent neurotoxic properties in cell cultures blocked either by NMDA antagonists or calcium channel antagonists. Moreover, human monocytoid cell lines infected by HIV release endogenous toxic factors with comparable cellular actions. We have analysed the effects of riluzole, a compound reducing the excitatory amino acid release on gp120-induced neurotoxicity in primary neuronal cultures. Riluzole, which blocks the release of glutamate and aspartate from nerve terminals, prevents (10(-7) M) the neuronal degeneration produced by 20 pM of gp120 in cortical cell cultures. This result could suggest that toxic factors produced by activated macrophages might increase glutamate release, and that this may be prevented by riluzole.
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PMID:Prevention of HIV coat protein (gp120) toxicity in cortical cell cultures by riluzole. 785 17

Previous studies on the variation of an immunodominant HLA-B27-restricted HIV-1 gag p24 epitope (KRWIIL GLNK, amino acids 263-272) have demonstrated the persistence of variants recognized by CTL. Sequence comparisons of HIV isolates showed that this region is relatively conserved and as a consequence might restrict antigenic variation. To evaluate the possibility of HIV-1 to yield infectious mutants of this epitope that lack the ability to bind to HLA-B27 or escape HLA-B27-restricted CTL recognition, single-point mutations were constructed in the infectious molecular clone of HIV-1 Lai. Changes of arginine 264, the anchor amino acid for HLA-B27, to lysine or glycine resulted in infectious HIV-1 variants. The respective synthetic peptides showed reduced ability to sensitize target cells for CTL recognition and a corresponding loss of binding affinity to HLA-B27. In contrast, mutation of glycine 269 to lysine or glutamate abrogated HIV-1 infectivity. The corresponding peptides were able to bind to HLA-B27 but were not recognized by CTL. These data show that HIV-1 tolerates some genetic variation of the HLA-B27-restricted CTL epitope in gag p24 and that single-point mutations can alter quantitatively the immunologic properties. Further, it demonstrates that the mere nonrecognition of peptides derived from quasispecies analysis of small regions might simply correspond to nonviable virus variants and cannot be taken as evidence for CTL escape mutants. Together with the previously published data on the persistence of CTL epitopes, these results suggest that CTL do not play a major role in driving HIV-1 evolution in vivo.
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PMID:Sequence constraints and recognition by CTL of an HLA-B27-restricted HIV-1 gag epitope. 786 92

The absence of AIDS-like symptoms in HIV-infected chimpanzees and SIV-infected African Green monkeys (AGMs) may provide important clues about the pathogenic mechanism of AIDS and about mechanisms of resistance. HIV-infected persons and SIV-infected rhesus macaques have, on the average, markedly decreased cysteine, cystine, and glutathione levels and elevated plasma glutamate concentrations. Glutamate inhibits the membrane transport of cystine and a combination of low plasma glutamate and high cystine levels was found to be correlated with high CD4+ T cell numbers even in HIV-negative healthy human individuals. We have now found that glutamate and cystine levels are also correlated with CD4+ T cell numbers in chimpanzees. But infection of chimpanzees, AGMs, and goats with HIV-1, SIV, and caprine arthritis encephalitis virus (CAEV), respectively, does not induce significant changes in plasma cystine or glutamate levels, although infected AGMs and goats have, on the average, significantly elevated plasma levels of the biochemically related amino acid proline.
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PMID:Plasma amino acid dysregulation after lentiviral infection. 790 43

1. HIV gp120 selectively reduces the glutamate-induced inward current and the acetylcholine-induced outward current in specific and identified Aplysia neurons without affecting dopamine (DA)- and serotonin (5-HT)-induced responses. 2. gp120 specifically decreases DA levels without significantly altering norepinephrine and 5-HT levels in Mytilus pedal ganglia. 3. The gp120-associated decrease in DA levels in Mytilus is dose dependent and exhibits a threshold level. 4. The alteration of in vitro DA levels is specific for gp120 since anti-gp120 blocks the effect. 5. gp120 and its effects appear to be stable due to the duration of treatment and the failure of secondary effects to materialize following antibody treatment.
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PMID:Selective effects of human immunodeficiency virus (HIV) gp120 on invertebrate neurons. 791 Jul 80

The third variable domain (V3 domain) of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is a major determinant of phenotypic variability. The V3 domain of HIV-1 has many basic amino acid residues. Lymphocytotropic HIV-1 tends to have a V3 domain with a higher density of positive charge than does monocytotropic HIV-1. The importance of basic residues in the V3 domain for the HIV-1 infectivity, however, has not been well investigated. Here we show that mutation of basic amino acid residues at positions 303, 306, 309, 313, and 325 in the V3 domain of the lymphocytotropic isolate NL4-3 results in a dramatic elimination of both virus infectivity and syncytium-inducing ability. Three basic amino acid substitutions (at position 306, 309, and 313) induced a decrease in the binding ability of two kinds of neutralizing antibodies (NEA9284 and 0.5 beta) that recognize a different site in the V3 domain. This suggests that the basic residues play an important role in maintaining the tertiary structure of the V3 domain. Monocytotropism was not simply dependent on either decreased positive charge in the V3 domain of NL4-3 or on mutation of lysine to glutamate at position 320, which is a characteristic amino acid of monocytotropic HIV-1. These findings contribute to our understanding of the significance of basic residues on the function of envelope glycoprotein.
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PMID:HIV type 1 infection of CD4+ T cells depends critically on basic amino acid residues in the V3 domain of envelope glycoprotein 120. 798 86


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