PROJECT SUMMARY Long-lived latently infected cells present a major obstacle to curing HIV infection; however, the upstream biochemical processes and signal transduction events that favor active HIV replication versus latent infection are poorly understood. We hypothesize that quality of signals at the time of infection is critical for establishing HIV latency. To investigate how signals contribute to productive or latent HIV infection we will use chimeric antigen receptors to modulate signaling at the time of infection. In addition, we will explore the cross talk between T cell receptor signaling cascades and those delivered across the virological synapse during cell-cell transmission of HIV. We are proposing the following three specific aims: 1) how does differential signaling influence HIV-1 infection of T cells; 2) identifying signaling events that are required for HIV infection; and 3) determine whether antigen receptor signal strength at the virological synapse influences HIV infection. In addition to the hypothesis, innovative aspects of this proposal include the interdisciplinary approach, which uses cellular, molecular and bioengineering tools to identify key regulatory networks that influence HIV infection. These studies will provide new insights into key regulatory networks that govern the establishment of HIV infection and latency. Furthermore, understanding the minimal requirements for T cell signaling and HIV infection will potentially identify novel cellular targets which could be manipulated in an effort to alter the size of the latent reservoir and the course of HIV/AIDS progression.