Human immunodeficiency virus type 1 (HIV-1) infection induces the depletion of the CD4-positive T cells in infected persons, leading to AIDS. The currently available treatments for HIV-1 infection do not cure the infection, display many side effects, lead to drug resistance, and are expensive. Consequently, there is a real need to further define the cell host/virus interactions that are either required for viral replication, or are capable of controlling infection. Little is known regarding the changes in cellular gene and microRNA expression that occur in host cells in response to HIV-1 infection. I propose to conduct detailed, time-dependent genome wide analyses of human gene expression in primary cells following HIV-1 infection, by using a combination of micro-arrays and deep sequencing methods. This study will be conducted in primary blood cells (the natural targets of HIV-1 infection) such as resting or activated CD4-positive T cells, monocyte-derived macrophages and monocytes. Reverse transcription in combination with quantitative real-time PCR will be used to validate observed changes in host gene expression. I plan to identify both the viral determinants and the cellular signal transduction pathways responsible for altered gene expression. Finally, I will analyse the functional relevance of the mRNAs and microRNAs induced, with respect to the potential control or suppression of HIV-1 infection. This work will provide new information on the interactions between HIV-1 and infected cells, on the ability of host cells to respond rapidly to virus infection, and on mechanisms of cell-mediated resistance to infection.
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