The influence of T cell receptor signaling on human immunodeficiency virus infection
Herring, Melissa Beth
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A significant barrier to curing Acquired Immunodeficiency Syndrome (AIDS) is the presence of latent reservoirs of cells infected with an integrated but transcriptionally silent provirus that is unaffected by the immune response or by antiretroviral drugs. Therefore, while antiretroviral therapy is able to suppress patient viral loads to clinically undetectable levels, upon cessation of treatment, viral loads rebound rapidly as virus is released from the latent reservoir. An understanding of the Human Immunodeficiency Virus (HIV) transcriptional regulatory events that contribute to viral latency is an important step towards eradicating the latent reservoir. Of particular interest are the mechanisms early in HIV infection that direct the cell towards productive or latent infection. The current study aims to determine whether the strength of T cell receptor (TCR) signaling at the time of HIV infection is correlated with the level of HIV transcription and to characterize the T cell receptor signaling pathways that regulate HIV transcription. We hypothesize that the strength of signaling at the time of infection determines the magnitude of early HIV transcription. Simultaneous infection and stimulation of Jurkat E6.1 T cells expressing the C6.5 chimeric antigen receptor shows a 1.5-fold increase in transcription compared to unstimulated controls while Jurkat E6.1 T cells expressing the B1D2 chimeric antigen receptor shows a nearly 3-fold increase in transcription compared to unstimulated controls. These results suggest that the strength of signaling through the TCR at the time of infection determines the magnitude of HIV transcription early in infection and may contribute to the establishment of productive or latent infection within the cell. Simultaneous infection and stimulation of Jurkat E6.1 T cells expressing the C6.5 or B1D2 chimeric antigen receptors in the presence of select inhibitors of T cell receptor signaling molecules indicate that TCR signaling through PI3 kinase and protein kinase C pathways may negatively and positively regulate HIV transcription, respectively. Understanding the specific TCR signaling pathways that lead to the initial establishment of latency within newly infected cells may lead to the discovery of novel therapeutic targets aimed at eliminating the latent reservoir.