Mucosal Epithelium and Long-Term Anti-Retroviral Therapy

描述（由申请人提供）：人类免疫缺陷病毒（HIV）感染与导致免疫缺陷和AIDS的CD4 T细胞的进行性丧失相关，并伴有许多机会性感染的出现。口腔粘膜是继发性感染如由爱泼斯坦巴尔病毒（EBV）引起的继发性感染的主要部位。EBV在免疫抑制患者中引起口腔毛状白斑（OHL），并且已经显示在来自OHL病变的上皮细胞中活跃地复制。相比之下，来自没有免疫抑制的患者的上皮细胞不显示活跃的病毒感染。这表明，HIV感染相关的上皮微环境的变化导致EBV的重新激活。尽管抗逆转录病毒疗法（ART）的出现对控制艾滋病毒感染产生了重大影响，并降低了机会性感染的发生率，但研究表明，使用ART的患者最终未能控制艾滋病毒感染。这种未能控制病毒血症与机会性感染如EBV相关OHL的再次出现有关。 在HIV感染和ART期间，导致EBV在口腔上皮细胞中活跃复制的确切机制和因素尚未阐明。该提案的总体目标是通过将上皮细胞功能和T细胞反应的变化与EBV的再活化相关联来描述长期ART期间口腔粘膜中EBV再活化的机制。 本研究将使用实验性感染猴免疫缺陷病毒（SIV）并接受抗逆转录病毒治疗（PMPA和FTC）的恒河猴。具体目标1将评估ART对宿主口腔上皮细胞因子的影响以及这些因子的变化如何与EBV的再活化相关，具体目标2将确定ART对EBV特异性T细胞应答的影响，目的是将EBV再活化与EBV特异性T细胞应答的失败相关联。这些研究将为长期ART期间EBV发病机制提供有价值的见解，并有助于确定新的治疗靶点以控制HIV感染受试者中的EBV感染。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infection is associated with a progressive loss of CD4 T cells leading to immunodeficiency and AIDS, and is accompanied by the emergence of numerous opportunistic infections. Oral mucosa is a primary site for secondary infections such as those caused by Epstein Barr Virus (EBV). EBV causes oral hairy leukoplakia (OHL) in immunosuppressed patients and has been shown to actively replicate in the epithelial cells from OHL lesions. In contrast, epithelial cells from patients who are not immunosuppressed do not show active viral infection. This would suggest that HIV infection associated changes in the epithelial microenvironment leads to the reactivation of EBV. Though the advent of anti-retroviral therapy (ART) has had a significant impact on controlling HIV infection and has led to a lower incidence of opportunistic infections, studies have shown that patients who use ART eventually fail to control HIV infection. This failure to control viremia is associated with the reemergence of opportunistic infections such as EBV associated OHL. The exact mechanisms and the factors that lead to active replication of EBV in oral epithelial cells during HIV infection and ART have not been elucidated. The overall objective of this proposal is to delineate the mechanisms of EBV reactivation in the oral mucosa during long-term ART by correlating changes in epithelial cell function and T cell responses with the reactivation of EBV. Rhesus macaques experimentally infected with simian immunodeficiency virus (SIV) and treated with anti-retroviral therapy (PMPA and FTC) will be used in this study. Specific aim 1 will evaluate the effect of ART on host oral epithelial cellular factors and how changes in these factors correlate with reactivation of EBV, and Specific aim 2 will determine the effect of ART on EBV-specific T cell responses with the objective of correlating EBV reactivation with failure of EBV-specific T cell responses. These studies will provide valuable insights into the mechanisms of EBV pathogenesis during long-term ART and help identify novel therapeutic targets to control EBV infection in HIV infected subjects.