PROJECT ABSTRACT KSHV is both a commensal and pathogenic microorganism in the human host. Many studies have shown that KSHV is present in the saliva and oral cavity and can be transmitted through both oral and sexual transmission routes. In conditions of immune suppression e.g. HIV infection or immunosuppressive therapy, KSHV is associated with the development of sarcomas and lymphomas, including in the oral cavity. Although these diseases are usually seen in the context of immune suppression, even HIV- negative individuals can develop KSHV-associated cancers. Thus, it is clear that the host immune system plays a critical role in preventing diseases associated with KSHV infection. It is currently unclear how the immune system keeps KSHV in check in healthy individuals, but allows disease to progress during times of immunosuppression. We have previously reported that TLRs, RLRs and NLRs are capable of detecting KSHV in a variety of different biologically relevant cell types during primary infection and during reactivation from latency. We also reported that the cGAS-STING DNA sensing pathway can detect KSHV during primary infection and reactivation and that KSHV viral proteins can counteract activation of this important pathway. In this application, we propose to determine how KSHV viral proteins modulate cGAS and STING innate immune proteins and allow the virus to successfully establish life-long latency in the human host. We also propose to examine how KSHV's modulation of innate immune pathways impacts HIV infection.