Mucosal Epithelium and Long-Term Anti-Retroviral Therapy

粘膜上皮和长期抗逆转录病毒治疗

基本信息

批准号：
7277094
负责人：
Joseph John Mattapallil
金额：
$ 30.56万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7277094
关键词：
Acquired Immunodeficiency Syndrome Anti-Retroviral Agents Architecture Autopsy B-Lymphocytes Biological Assay Blood specimen CD14 gene CD3 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cell Count Cell physiology Cells Color Defect Defense Mechanisms Disease Drug resistance Epithelial Epithelial Cells Epithelium Epstein-Barr Virus Infections Epstein-Barr pathogenesis Evolution Failure Flow Cytometry Frequencies Gagging Gene Expression HIV Hairy Leukoplakia Highly Active Antiretroviral Therapy Hour Human Herpesvirus 4 Immunocompromised Host Immunologic Deficiency Syndromes Immunosuppressive Agents Incidence Individual Infection Integrins Interferons Kaposi Sarcoma Kinetics Lead Lesion Leukocytes Long-Term Effects Longevity Lymphocryptovirus Lytic MS4A1 gene Macaca mulatta Measures Mediating Microarray Analysis Molecular Profiling Mucous Membrane Natural regeneration Nature Numbers Opportunistic Infections Oral Oral Leukoplakia Oral Manifestations Oral candidiasis Oral mucous membrane structure PTPRC gene Pan Genus Pathogenesis Patients Pattern Peptides Phenotype Play Polymerase Chain Reaction Process Proteins Relative (related person)Role SIV Saliva Sampling Site Sorting - Cell Movement Staining method Stains Surface T-Lymphocyte T-Lymphocyte Subsets TNF gene TNFSF5 gene Testing Thinking Time Tissues Toxic effect Transforming Growth Factors Viral Viremia Virus Diseases Virus Replication base cell mediated immune response cytokine immunosuppressed infected B cell insight macrophage monocyte novel therapeutics oral cavity epithelium peripheral blood pinacolyl methylphosphonic acid response secondary infection success therapeutic target

项目摘要

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.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）感染与CD4 T细胞的进行性丧失有关，导致免疫缺陷和艾滋病，并伴随着许多机会性感染的出现。口服粘膜是继发性感染（例如由爱泼斯坦Barr病毒（EBV）引起的）的主要部位。 EBV在免疫抑制患者中引起口服毛状白细胞（OHL），并已被证明会在OHL病变的上皮细胞中积极复制。相比之下，未经免疫抑制的患者的上皮细胞不会显示活性病毒感染。这表明HIV感染相关的上皮微环境变化会导致EBV的重新激活。尽管抗逆转录病毒疗法（ART）的出现对控制HIV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HIV感染。这种无法控制病毒血症的失败与机会性感染（例如EBV相关OHL）的重新出现。尚未阐明在HIV感染和ART期间口服上皮细胞中EBV主动复制的确切机制和因素。该提案的总体目的是通过将上皮细胞功能和T细胞反应的变化与EBV的重新激活相关联，来描述长期ART期间口腔粘膜中EBV重新激活的机制。本研究将使用恒河猴实验感染，并用抗逆转录病毒治疗（PMPA和FTC）治疗。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与EBV的重新激活的相关性如何，而具体目标2将决定ART对EBV特异性T细胞反应的影响，并与EBV特异性T细胞反应的失败相关联。这些研究将为长期艺术期间EBV发病机理的机制提供宝贵的见解，并有助于确定新的治疗靶标，以控制HIV感染受试者中EBV感染。