An important but little-studied aspect of viral pathogenesis is the effect of interactions between viruses within specific compartments, such as primary or secondary lymphoid organs, or the oral cavity. More than 95% of us are infected with more than one of the eight human herpesviruses. Childhood infections of most of these viruses, such as herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), human herpes viruses 6 and 7 (HHV-6 and HHV-7), Epstein-Barr virus (EBV), human cytomegalovirus (CMV), result in mild or asymptomatic diseases. Unlike many virus pathogens, herpesviruses are not completely cleared from the body after the primary infection. Well known as opportunistic pathogens, herpesviruses are able to remain latent for years, and then reactivate during periods of immune suppression, often causing more serious diseases among individuals who have had organ transplants, are undergoing chemotherapeutic cancer treatments, or are HIV-1-infected and developing AIDS. The research goals of the Duus laboratory are to understand the effects of childhood viral infections on immune system development and subsequent immune responses throughout life, which remain poorly understood. Ultimately, this knowledge would be employed to manipulate the immune response, design more effective gene therapy vectors, and generate viral protein-based pharmaceuticals to curtail and/or cure both viral and nonviral diseases. Much can be learned about the molecular mechanisms of host immune response development by comparing effects of nonpathogenic and pathogenic lymphotropic viral infections on gene expression in primary and secondary lymphoid tissues, and in the lymphoid and epithelial tissues of the oral cavity, where many viruses reside, and where many initial exposures to pathogenic and nonpathogenic organisms occur. HIV-1 and herpesviruses target common cell populations in tissues of the oral cavity and the immune system, strongly suggesting that co-infection of cells and/or tissues occurs in HIV-infected individuals. However, the interactions of these viruses have not been extensively studied at the molecular level. The objectives of the studies in the Duus laboratory are to i) develop a dual explant infection model with which to ii) analyze the consequences of HIV-1 and variously pathogenic herpesvirus co-infections on HIV-1 replication and pathogenesis in lymphoid and epithelial tissues of the oral cavity, and to iii) elucidate the molecular mechanism(s) involved in the interaction(s) between these viruses. The central hypothesis of these studies is that alterations in virus infectivity, replication and/or pathogenesis in herpesvirus/HIV co-infected tissues of the oral cavity are mediated by interactions which influence cell signaling pathways. The rationale of the studies is based on i) the shedding of HIV-1 and most herpesviruses in the oral cavity, and ii) the miriad effects of these viruses on many host cell signaling pathways. A better understanding of the mechanisms of HIV-1 interactions with opportunistic herpesviruses may lead to the development of novel therapeutic targets against both retroviral and herpesviral pathogens.