Oral immune plasticity, HIV-infected T cell extracellular vesicles, and oral cancer

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ABASTRACT HIV-infected individuals under combination antiretroviral therapy (cART) have approximately 2- to 6-fold increased incidence rates of oral cancer relative to the general population. These trends in the cART era are implicitly attributed to persistent and residual HIV replication that induces oral inflammation for tumor progression. The success of new approaches to control tumorigenesis in the population is contingent to identifying HIV-specific mechanisms that facilitate tumor development and progression. HIV-infected T cells produce a variety of immunologically active extracellular vesicles (EVs) to influence intercellular communication and regulate immune response at both local and distant sites, thus contribute to oral immune system plasticity. Our preliminary studies explicitly suggest involvement of EVs from HIV-1-infected T cells in oral cancer progression: 1) HIV-1-infected and control T cells secreted tetraspanin- and acetylcholinesterase- positive EVs, indicating presence of exosomes in the EV preparation; 2) HIV-infected T cell EVs, but not control ones, significantly stimulated oral cancer cell proliferation and migration in vitro and tumor growth in vivo; 3) HIV-infected T cell EVs stimulated ERK phosphorylation without epidermal growth factor receptor phosphorylation; 4) cART inhibited EV release; 5) EV proteins and miRNA were differentially expressed in latently HIV-1-infected T cells and control T cells. Taken together, these data are consistent with our hypothesis that HIV-infected T cell EVs can promote oral cancer development and progression in HIV-infected individuals under cART and that HIV+ EVs may serve as a target for novel therapeutic approaches to control oral tumorigenesis in the population. We will test the hypothesis with specific aims to 1) delineate the mechanism by which HIV-1-infected T cell EVs stimulate oral cancer cell growth and progression. We will identify signaling pathways of cancer cells that respond to HIV-infected and non-HIV T cell EVs for cell proliferation, migration, and invasion; 2) identify functional EV production and cargo content in latently HIV- infected T cell EVs in response to cART. We will investigate how cART affects EV release and conduct proteomics, miRNomics, and lipidomics to access EV molecular signatures that differentiate HIV-infected from non-HIV T cells. This proposed research will expand knowledge on oral immune system plasticity mechanisms for developing preventive and therapeutic approaches.