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Title: Cytokine regulation of human immunodeficiency virus type 1 gene expression in cells of neural origin
Author: Swingler, Simon
ISNI:       0000 0001 3494 3128
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 1991
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In response to the growing body of evidence suggesting the direct infection of neural cells may contribute to the pathogenesis of the neurological syndrome associated with HIV infection, the AIDS dementia complex, the regulation of HIV-1 gene expression by cytokines was investigated in cells of central nervous system origin. Expression from a reporter gene under the control of the HIV-1 LTR was determined by transient transfection assays in a collection of cells representative of the major neural components of the central nervous system. These were human neuroblastoma, astrocytoma, glioblastoma cell lines, primary murine astrocyte cultures and a murine oligodendroglioma cell line. Cellular stimulation with a range of cytokines, TNFα, IL-1β IL-6, IFNα and IFNγ, individually and in pairs revealed a number of these capable of significantly augmenting expression from the LTR. TNFα was found to stimulate LTR-driven gene expression in all neural cells as did IL-1β in astrocytoma, glioblastoma and astrocyte cultures. IL-6 enhanced expression only in astrocyte cultures. The interferons generally suppressed LTR-driven gene expression except IFNγ which consistently augmented expression in murine astrocyte and oligodendroglioma cells and IFNα augmenting reporter gene expression in one neuroblastoma cell line. The HIV-1 tat gene product was found to be functional in all cell types with varying degrees of efficient^ and in one cell line the combination of an activating cytokine or phorbol ester and Tat resulted in an enhancement above that obtained by co-transfection with Tat alone. In most the level of expression did not significantly change. Analysis of the interaction of sequence-specific DNA-binding proteins with the HIV-1 LTR demonstrated that in both neuroblastoma and astrocytoma cells the augmentation of LTR-driven gene expression by TNFα or IL-1β correlated with the induction of factors recognizing the NFxB motifs of the HIV enhancer. These proteins were rapidly induced and no other DNA-binding activities recognizing the LTR were found to be regulated by cytokines. Many constitutive DNA-binding factors were observed to interact with the LTR, such as LBP-1-, Spl1, TATA-, Site A- and Site B-like binding activities previously noted in lymphocytes and HeLa cells. In addition two neural specific factors were discovered which recognize octamer- and GTI-like binding motifs in the LTR. The results obtained demonstrate that the cytokines can regulate cellular mechanisms that can lead to augmented transcription from the HIV-1 LTR in neural cells and suggest that a latent infection of neural cells by HIV-1 will be activated by TNFα and IL-1β in the central nervous system of patients with the AIDS dementia complex.
Supervisor: Not available Sponsor: Medical Research Council ; Cancer Research Campaign
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology