Mucosal Epithelium and Long-Term Anti-Retroviral Therapy

描述(申请人提供)：人类免疫缺陷病毒(HIV)感染与CD4T细胞的进行性丧失有关，导致免疫缺陷和艾滋病，并伴随着大量机会性感染的出现。口腔粘膜是爱泼斯坦-巴尔病毒(EBV)等继发性感染的主要部位。EB病毒在免疫抑制患者中引起口腔毛状白斑(OHL)，并已被证明在OHL病变的上皮细胞中活跃复制。相比之下，来自没有免疫抑制的患者的上皮细胞不会显示出活跃的病毒感染。这可能表明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，并导致机会性感染的发生率较低，但研究表明，使用ART的患者最终无法控制艾滋病毒感染。这种控制病毒血症的失败与机会性感染的重新出现有关，例如EBV相关性OHL。 在HIV感染和ART过程中，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。这项建议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的重新激活联系起来，描述长期ART期间口腔粘膜中EBV重新激活的机制。 本研究以实验感染猴免疫缺陷病毒(SIV)并经抗逆转录病毒治疗(PMPA和FTC)治疗的恒河猴为研究对象。具体目标1将评估ART对宿主口腔上皮细胞因子的影响，以及这些因素的变化如何与EBV重新激活相关，而特定目标2将确定ART对EBV特异性T细胞反应的影响，目的是将EBV重新激活与EBV特异性T细胞反应失败联系起来。这些研究将为长期抗逆转录病毒治疗中EBV的发病机制提供有价值的见解，并有助于确定控制HIV感染者EBV感染的新治疗靶点。

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.