Human Immunodeficiency Virus-1 (HIV-1) infects CD4+ T cells, monocytes, and dendritic cells. Activation of HIV-1 infected cells leads to viral replication and, therefore, plays an important role in the progression of HIV-1 infection from a latent stage to an active stage. Monocytes, as a major reservoir of HIV-1, serve as a vehicle of dissemination to multiple organ systems. Infection of monocytes by HIV-1 has been shown to upregulate their expression of la molecules. The role of Ia molecules in the activation of HIV-1 gene expression in infected monocytes has not been investigated. Engagement of la molecules by bacterial superantigens and by antibodies causes the activation of la+ immune cells (monocytes, B cells, and activated T cells) and induces cytokine gene expression in these cells. Recent data indicates that la ligands also activate HIV-1 gene expression in monocytic cell lines. The mechanism of activation of HIV-1 gene expression by Ia ligands will be investigated. I. The activation of HIV-1 gene expression in monocytes by Ia ligands will be investigated using: 1. Transient transfection assays with an HIV-1-LTR-CAT vector. 2. Induction of HIV- 1 protein secretion from chronically infected cell lines. II. The role of NF-kappaB, AP- 1, Myb, and NFAT- 1 DNA response elements, present in the HIV- 1 -LTR, in Ia-induced HIV- 1 gene expression will be evaluated by studying the activation, by Ia ligands, of: 1. DNA-binding activity. 2. Transcription of mRNA for DNA-binding proteins. and by assessing the: 3. Promotor / enhancer activity of individual response elements. III. The Mechanism of induction of HIV-1 gene expression by Ia ligands will be investigated by evaluating: 1. The role of protein kinase C, protein tyrosine kinases, cyclic nucleotide dependent kinases, and Ca2+/calmodulin dependent kinases. 2. The role of protein tyrosine and serine/threonine phosphatases. The results of the proposed studies will enhance our understanding of the mechanism of induction of HIV-1 gene expression via Ia molecules. This may allow us to devise more rational therapeutic strategies-to prevent the progression of HIV-l disease.
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