PROJECT SUMMARY In the era of antiretroviral therapy (ART), people living with HIV (PLWH) have approximately 2- to 6-fold increased incidence rates of oral squamous cell carcinoma (OSCC) relative to the general population as they age. OSCC is preceded by premalignant disorders, specifically leukoplakia and erythroplakia, for a long time and the progression to cancer can be accelerated by various risk factors, including HIV infection. There is an urgent need to identify HIV-specific risk factors of OSCC progression in PLWH for prevention and assessment of treatment outcomes in the population. We have reported that HIV-infected immune cells release exosomes (small membrane extracellular vesicles of endocytic origin) to the extracellular space and body fluids for immune regulation and transferring HIV-specific cargo components to recipient cells, thus potentially contributing to transition of premalignant oral disorders to cancer. We have reported that exosomes released by HIV-infected T cells or those purified from the blood of PLWH stimulate proliferation, migration and invasion of oral cancer cells in vitro and enhance growth of OSCC xenograft tumors in vivo. HIV-associated exosomes also induce expression of proto-oncogenes in OSCC cells. The HIV TAR RNA is the major exosomal cargo component responsible for the pro-cancer effects of HIV-associated exosomes. Our preliminary data demonstrate that saliva exosomes derived from PLWH, but not those from healthy individuals, contain HIV TAR RNA and interact with the epidermal growth factor receptor (EGFR) to facilitate infection of Kaposi sarcoma-associated herpesvirus (KSHV) in oral epithelial cells. In addition, our extensive “exomics” approach have revealed specific molecular signatures of HIV-infected T-cell exosomes. Therefore, our published and preliminary results indicate that HIV-associated saliva exosomes potentially participate in pathogenesis of oral disorders, including non-communicable diseases (NCDs), and are risk factors for progression of premalignant oral epithelial lesions to cancers in PLWH. We hypothesize that HIV-associated exosomes in the saliva act as a risk factor for progression of premalignant oral lesions to cancer. In this proposed study, we will: 1) evaluate HIV TAR RNA-bearing saliva exosomes as a risk factor of premalignant oral lesions in PLWH and investigate the effect of HIV-positive and –negative saliva exosomes on oncogenic properties of leukoplakia cells and 2) investigate cargo components of the saliva and matched blood exosomes from PLWH and HIV negative persons for molecular signatures of HIV-associated saliva and matched plasma exosomes using the exomics approach.