PROJECT ABSTRACT Kaposi's sarcoma (KS) remains the most common tumor arising in patients with HIV/AIDS, and involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. HIV infection incurs an increased risk for periodontal diseases and oral carriage from a variety of pathogenic bacteria. However, whether interactions involving periodontal bacteria and oncogenic viruses in the local environment facilitate replication or maintenance of these viruses in the oral cavity remains largely unknown. Our published and preliminary data indicate that incubation of human primary oral cells with two prototypical pathogen-associated molecular patterns (PAMPs) produced by prominent periodontal bacteria—lipoteichoic acid (LTA) from Staphylococcus aureus (Sa) and lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg)—increases initial viral entry and subsequent latent gene expression during de novo KSHV infection. Moreover, LTA and LPS up-regulate one of cellular receptors for KSHV entry, Heparan sulfate proteoglycan (HSPG) and increase reactive oxygen species (ROS) production as co-factor contributed to KSHV infection. Additionally, we found that conditioned medium from Sa and Pg culture or bacterial PAMPs induced viral lytic reactivation from latently infected oral cells through regulation of viral microRNAs expression, promoting virus dissemination. For clinical relevance, we found a high infection and co-infection rate of Sa, Pg and KSHV in the oral cavity of our cohort of HIV+ patients, and found higher levels of salivary ROS, host antioxidant factors and bacterial LTA/LPS from HIV+/KSHV+ patients than those HIV+/KSHV- ones. Based on these data, we hypothesize that periodontal bacteria or their PAMPs may facilitate initial KSHV infection, replication and dissemination in the oral cavity of HIV+ patients through multiple host and viral factors, and ultimately promote oral KS development. To address this hypothesis, we propose the following specific aims including both clinical and basic studies: 1) Determine the clinical relevance and correlations between host salivary antioxidant factors, specific bacterial carriage/PAMPs levels, and KSHV oral shedding in HIV+ patients. 2) Identify the mechanisms through which periodontal bacteria or their PAMPs facilitate KSHV initial infection and viral lytic reactivation, two important steps necessary for KS development. Through these efforts, we can better understand how pathogens co-infection can promote virus-associated cancer development in oral unique niche of immunocompromised patients. Our results will also provide the framework for the development of clinical trials evaluating the strategies interfering with host-bacteria-virus interaction (e.g. specific antibiotics, targeting TLRs-ROS axis or viral microRNAs synthesis) for their abilities to reduce or prevent oral KSHV infection and KS progression in HIV+ patients.