Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

The pathology of AIDS is strongly influenced by control of HIV-1 gene expression through immune cell (T cell) activation signals. During the course of infection, a population of latently infected resting memory T cells develop which contain transcriptionally repressed, chromosomally integrated copies of the HIV genome. These latently infected cells contribute to disease progression by acting as reservoir of inducible virus production throughout the course of infection. Furthermore, latent provirus is unaffected by current AIDS drugs and, without new therapies that target this specific latent population, the virus can never be eliminated from infected individuals. Expression of viral genes is controlled by the long terminal repeat (LTR) promoter, which has binding sites for numerous transcription factors present in T cells. Our research has identified a factor termed RBF-2, which binds at two places on the viral promoter. We have proposed that RBF-2 regulates the establishment of latency and re-activation in response to T cell signalling by controlling chromatin organization at the LTR which, in turn, influences access of additional transcription factors to the viral enhancer region. Considering the importance of RBF-2 for regulation of the integrated provirus, we aim to characterize specific interactions between RBF-2 proteins that enable recognition of its conserved binding sites on the viral promoter, identify mechanisms for regulation of these factors by T cell signaling, and determine their role in regulating chromatin organization around the latent provirus. Additionally, we plan on using novel protein-protein interaction technology developed in our lab to identify specific inhibitors of RBF-2, with the expectation that these will be useful in treating the latently infected memory T cell population. Moreover, we will investigate the usage of LTR mutants, which show a higher basal level of HIV gene expression, in the development of a novel HIV vaccine.