Towers, Gregory John; (1995) The control of human immunodeficiency virus type 1 long terminal repeat promoter activity by retinoic acid. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The control of human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) directed gene expression by the hormone all-trans-retinoic acid has been investigated. Cell type specific positive and negative modulation of basal and phorbol ester induced HIV-1 promoter activity is demonstrated. These effects of retinoic acid, shown to be dependent on retinoic acid nuclear receptors, are mapped to the NF-kB and Sp-1 binding region. Retinoic acid is shown to inhibit basal and phorbol ester stimulated HIV-1 promoter activity in the human promonocyte cell line U937 and in the human cervical carcinoma cell line HeLa. Phorbol ester stimulated gene expression from a heterologous promoter enhanced by multimers of NF-kB sites, from either the HlV-1 LTR or the human interleukin-2 gene, or the mouse major histocompatibility complex H2k gene, is also inhibited by retinoic acid. Furthermore, the activation of the HIV-1 promoter by the HlV-1 transactivator protein that is shown to be inhibited by retinoic acid. Retinoic acid is also demonstrated to inhibit the stimulation of HIV-1 promoter activity by expression of NF-kB in the human T cell line Jurkat but, conversely, to synergise with the stimulation by phorbol ester treatment. Finally, retinoic acid receptor α is shown to be able to bind specifically to the HlV-1 NF-kB site in vitro, in the presence of the retinoic acid X receptor β. The mechanisms of the cell type specific positive and negative regulation of the HIV-1 promoter are discussed.

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