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Biomedical subjects

K E Nye

Publications and source records attributed to K E Nye.

8 recordsLinked to original sources
PubMed1992

The defect seen in the phosphatidylinositol hydrolysis pathway in HIV-infected lymphocytes and lymphoblastoid cells is due to inhibition of the inositol 1,4,5-trisphosphate 1,3,4,5-tetrakisphosphate 5-phosphomonoesterase.

Lymphocytes infected in vivo with HIV or lymphoblastoid cells exposed in vitro to either HIV or its envelope glycoprotein (gp120) show a defect in inositol polyphosphate-mediated signal transduction together with an associated abnormality in intracellular calcium regulation. The defect in patients reverses after treatment with the anti-retroviral agent zidovudine (AZT). We present evidence that the defect is at the level of the Ins (1,3,4,5)P4 5-phosphomonoesterase (PME) in these cells and that, though elevation of the intracellular ATP level partially down-regulates the activity of this enzyme, such changes alone are unable to account for the complete inhibition seen in HIV-infected cells.

Adenosine Triphosphate↗
PubMed1992

Impaired degradation of Ca(2+)-regulating second messengers in myeloid leukemia cells. Implications for the regulation of leukemia cell proliferation.

Inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate are Ca(2+)-regulating second messenger molecules which are generated via the cleavage of inositol lipids. We have previously shown that these species are autonomously generated in HL60 myeloid leukemia cells and that they may play a role in signalling the continuous proliferation of this cell line. Here we show that the activity of the 5-phosphomonoesterase (5-PME) enzyme which cleaves and inactivates these second messengers was strikingly reduced in HL60 cells compared to normal granulocytes or macrophages. Induction of differentiation of HL60 cells along the monocyte/macrophage or granulocytic pathways did not result in a significant increase in 5-PME activity. The activity of this enzyme was also low in extracts of bone marrow mononuclear cells from four patients with myeloid leukemia. A lesion in the 5-PME pathway may therefore result in the conservation of Ca(2+)-regulating second messengers in the HL60 cell line and in some myeloid leukemia cells. It is plausible that this lesion may co-operate with the autonomous cleavage of inositol lipids in the signalling of leukemic cell proliferation.

Bone Marrow↗
PubMed1991

Lymphocytes from HIV-infected individuals show aberrant inositol polyphosphate metabolism which reverses after zidovudine therapy.

Lymphocytes or lymphoblastoid cells that have been infected by HIV in vitro or exposed to its envelope glycoprotein (gp120) show abnormal inositol polyphosphate-mediated signal transduction and associated defects in calcium regulation. Such cells behave as though they were chronically activated and fail to respond to further activating signals. We now show that similar changes are seen in lymphocytes obtained from HIV-infected subjects at various stages of infection, despite the fact that only a minority of such cells are infected. Furthermore, the defect in the phosphatidylinositol hydrolysis pathway in lymphocytes obtained from AIDS patients reverses after treatment with zidovudine, in parallel with improvements in phytohaemagglutinin-induced proliferative response and interferon-gamma production.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Defective signal transduction--a common pathway for cellular dysfunction in HIV infection?

Qualitative defects in immune responsiveness after human immunodeficiency virus (HIV) infection have been well characterized and may play a key role in the development of HIV disease. However, no clear picture of the underlying mechanism of the functional deficiencies has yet emerged. In this article, Anthony Pinching and Keith Nye suggest that HIV or HIV proteins can sabotage transmembrane signalling and that this is of primary importance to the alterations in immune responsiveness.

CD4-Positive T-Lymphocytes↗
PubMed1990

HIV infection of H9 lymphoblastoid cells chronically activates the inositol polyphosphate pathway.

Infection with HIV causes a reduction in the numbers and function of CD4+ lymphocytes and functional abnormalities of other cells. We have studied the effect of HIV infection on signal transduction in the H9 lymphoblastoid CD4+ cell line. Resting HIV-infected H9 cells show evidence of chronic activation with raised levels of InsP3 and InsP4, the active metabolites of the inositol polyphosphate pathway, and a consequently raised intracellular free calcium concentration. Stimulation of HIV-infected H9 cells with phytohemagglutinin (PHA) leads to a fall in the previously raised levels of InsP3 but a further rise in InsP4, whilst an attenuated intracellular calcium rise is seen with both PHA and anti-CD3 antibody. The observed effects of HIV infection on signal transduction provide a mechanism to explain the functional defects in CD4+ lymphocytes and, possibly, other cell types.

CD4-Positive T-Lymphocytes↗
PubMed1989

An association between Gc (vitamin D-binding protein) alleles and susceptibility to rheumatic fever.

Rheumatic fever is associated with exaggerated activity of B cells with massive production of antibody to the Group A streptococcus. Gc (vitamin D-binding protein) is constitutively expressed on B-cell membranes in association with membrane immunoglobulin, and could be involved in cell activation. We therefore looked for associations between the three major Gc alleles and susceptibility to rheumatic fever in a homogeneous Arab population. Patients with tuberculosis or rheumatoid arthritis and control donors, were studied in parallel. Allele frequencies in the controls, rheumatoid and tuberculosis patients were identical to those found in a previous study of normal Arab donors. However, there was a striking association between Gc2 and rheumatic fever. This allele was twice as common in these patients as in controls (p = 0.0024), and was present in 56.4% of all rheumatic fever patients.

Alleles↗
PubMed1987

Association of different allelic forms of group specific component with susceptibility to and clinical manifestation of human immunodeficiency virus infection.

The distribution of phenotypes of the group specific component (Gc) was examined in 203 homosexuals at risk of infection or infected by the human immunodeficiency virus and compared with that in 50 randomly selected homosexuals and 122 healthy male heterosexual seronegative controls. 30.2% of patients with the acquired immunodeficiency syndrome (AIDS) were homozygous for Gc 1 fast (Gc 1f) compared with 0.8% of controls (p less than 0.0001); patients with other clinical manifestations of HIV infection were also more likely than controls to have Gc 1f. By contrast, seronegative symptomless homosexual contacts of AIDS patients (AH-p) lacked this phenotype but were more likely than controls to be homozygous for Gc 2 (25% vs 9%, p less than 0.05). AIDS patients lacked the homozygous Gc 2 phenotype altogether. A chi 2 trend test showed that progression to AIDS had a strong positive association with the Gc 1f allele (p less than 0.0001) and a negative one with Gc 2 (p less than 0.05). It is proposed that Gc may be involved in viral entry into host cells, the ease of which varies with different allelic forms of Gc, according to their sialic acid content.

AIDS-Related Complex↗