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

AbastRACT 接受联合抗逆转录病毒治疗（cART）的艾滋病毒感染者， 口腔癌的发病率相对于一般人群有所增加。cART时代的这些趋势是 隐含地归因于持续和残留的HIV复制，其诱导肿瘤的口腔炎症 进展控制人群肿瘤发生的新方法的成功取决于 确定促进肿瘤发展和进展的HIV特异性机制。HIV感染的T细胞 产生多种免疫活性细胞外囊泡（EV）以影响细胞间 沟通和调节免疫反应在本地和远程网站，从而有助于口腔免疫 系统可塑性我们的初步研究明确表明，来自HIV-1感染的T细胞的EV参与了 口腔癌进展：1）HIV-1感染的和对照的T细胞分泌四跨膜蛋白和乙酰胆碱酯酶， 阳性EV，表明EV制剂中存在外来体; 2）HIV感染的T细胞EV，但不 对照组在体外显著刺激口腔癌细胞增殖和迁移， 体内; 3）HIV感染的T细胞EV刺激ERK磷酸化而无表皮生长因子受体 磷酸化; 4）cART抑制EV释放; 5）EV蛋白和miRNA在细胞中的差异表达。 潜伏HIV-1感染的T细胞和对照T细胞。综合起来，这些数据与我们的数据一致。 HIV感染T细胞EV可促进HIV感染者口腔癌发生和进展的假设 在cART下的个体和HIV+ EV可能作为新的治疗方法的目标，以控制 口腔肿瘤的发病率。我们将检验这个假设，具体目标是：1）描述 HIV-1感染的T细胞EV刺激口腔癌细胞生长和进展的机制。我们将 鉴定响应HIV感染和非HIV T细胞EV癌细胞的信号传导途径 增殖、迁移和侵袭; 2）鉴定潜伏性HIV-1中功能性EV产生和货物含量。 感染的T细胞EV响应cART。我们将研究cART如何影响EV的释放和进行 蛋白质组学、miRNomics和脂质组学，以获得区分HIV感染者和 非HIV T细胞这项拟议的研究将扩大对口腔免疫系统可塑性机制的认识 用于开发预防和治疗方法。

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.