BK Virus: Its role in BLL Causation

描述（由申请人提供）： HIV相关唾液腺疾病（HIVSGD）也称为良性淋巴上皮病变（BLL），是一种以艾滋病为特征的儿科疾病，高达40%的儿童受影响。即使在广泛使用高效抗逆转录病毒治疗后，BLL在成年人群中的患病率仍在增加，在发展中国家高达48%的成年人中检出。这种毁容，往往污名化，疾病严重影响生活质量（QOL）。BLL在相当一部分受影响的个体中先于受影响腺体中的癌症发展，并且易患猖獗的龋齿和进行性牙周病。潜在的病原体尚未确定，因此没有有效的治疗方法。本提案的主题是确定肿瘤诱导多瘤病毒BK（BKV）与BLL发展/恶化之间的关联。因此，1）分子流行病学研究应支持这种关联，2）BKV滴度应与疾病严重程度相关。为了实现我们的目标，我们的初步研究已经鉴定了BLL中的人多瘤病毒BK，1）在BLL中一致地检测到BK病毒基因产物，2）个体是病毒血症，和3）BKV在其口腔分泌物中以升高的水平脱落。我们已经开发了第一个体外BKV唾液腺细胞感染系统的生产性非溶解性感染，反映了疾病，并使BK感染的机制分析。使用BKV靶向抗病毒药物，我们可以在我们的体外模型中抑制BKV的复制。啮齿类动物感染同源多瘤病毒会导致这些动物发生类似的唾液腺疾病。总之，这些发现导致了以下特定目标的发展，这些目标将探索BKV在唾液腺病理学中的作用，并将定义BKV允许性唾液腺感染与BLL之间的关联。根据因果关系的分子指南，这些目标将通过AIM 1）进行BLL的前瞻性病例对照研究，其中将分析腺体和体液（唾液、血清、尿液、血浆、PBL，用于病毒区室化研究）中的BKV复制决定因素、抗BKV抗体状态和病毒基因表达。我们将BLL中的唾液功能（静息和刺激流）和唾液蛋白分泌与BKV滴度相关联。将在BLL组内进行一项初步随机对照试验。BLL集团将 目的2）在回顾性纵向研究中确定BLL是否是儿童原发性感染的表现。将对患有该疾病的HIV+BLL+儿童和匹配的暴露未感染对照进行评估。目的3）通过回顾性纵向研究，确定成人BLL是否是HAART启动刺激的再激活事件的结果。拟定的分子流行病学研究探讨了BKV产生的唾液腺细胞病变的可能性，这些病变影响对正常腺体功能至关重要的过程，并可能支持BKV和BLL之间的因果关系。我们在口服病毒发病机制和临床试验方面的专业知识将促进这一重要努力。 公共卫生相关性： 由于移植、自身免疫性疾病和艾滋病，许多美国人的免疫功能受到抑制。他们很容易被儿童时期获得的病毒重新激活，如BK病毒。我们在免疫抑制患者的唾液腺疾病（BLL）中检测到BKV。BLL引起继发于唾液腺功能障碍的龋齿和牙龈疾病，并可能先于唾液腺癌。我们试图确认BKV与BLL的关联，并了解BKV如何导致BLL。这种理解将允许目前不存在的治疗。

DESCRIPTION (provided by applicant): HIV associated salivary gland disease (HIVSGD) also known as benign lymphoepithelial lesion (BLL) is an AIDS defining pediatric disease with up to 40% of children affected. BLL prevalence is increasing in the adult population even after widespread use of highly active antiretroviral therapy and is detected in up to 48% of adults in the developing world. This disfiguring, often stigmatizing, disease drastically impacts quality of life (QOL). BLL precedes development of cancer in the affected gland in a significant portion of affected individuals and predisposes to rampant caries and progressive periodontal disease. The potential etiologic agent has not been identified hence, there are not effective therapies. The theme of this proposal to define the association between the tumor-inducing polyomavirus BK (BKV) and development/exacerbation of BLL. As such, 1) molecular epidemiologic studies should support this association and 2) BKV titers should correlate with disease severity. Towards achieving our goals, our preliminary studies have identified the human polyomavirus, BK in BLL 1) BK viral gene products were consistently detected in BLL, 2) individuals were viremic, and 3) BKV was shed at elevated levels in their oral secretions. We have developed the first in vitro BKV salivary gland cell infection system of productive non-lytic infection, mirroring the disease, and enabling mechanistic analyses of BK infection. Using BKV targeted antiviral drugs, we can inhibit replication of BKV in our in vitro model. Infection of rodents with homologous polyomaviruses cause similar salivary gland disease in these animals. Taken together these findings led to development of the following specific aims that will probe the role of BKV in salivary gland pathology and will define the association between BKV permissive salivary gland infection and BLL. Following molecular guidelines for causation, these aims will be achieved by AIM 1) To conduct a prospective case control study of BLL where BKV determinants of replication, anti-BKV antibody status, and viral gene expression will be analyzed in gland, and body fluids (saliva, sera, urine, plasma, PBL for study of viral compartmentalization). We will correlate salivary function (resting and stimulated flow) and salivary protein secretion in BLL with BKV titers. A pilot randomized control trial will be performed within the BLL group. The BLL group will be randomized to BKV targeted antiviral or placebo AIM 2) To determine if BLL is a manifestation of primary infection in children in a retrospective longitudinal study. HIV+BLL+ children with the disease and matched exposed uninfected controls will be assessed. AIM 3) To determine if BLL in adults is the result of a reactivation event stimulated by HAART initiation in retrospective longitudinal study. The proposed molecular epidemiologic studies explore the potential for BKV generated salivary gland cellular lesions that affect processes critical to normal glandular function and may lend support for causal association between BKV and BLL. Our expertise in oral viral pathogenesis and clinical trials will facilitate this important effort. PUBLIC HEALTH RELEVANCE: Many Americans are becoming immunosuppressed as a result of transplant, autoimmune disease and AIDS. They are susceptible to reactivation of viruses acquired during childhood, like BK virus. We have detected BKV in salivary gland disease (BLL) of immune suppressed patients. BLL causes dental caries and gum disease secondary to salivary gland dysfunction and may precede salivary gland cancer. We seek to confirm BKV's association with BLL and understand how BKV causes BLL. This understanding will allow treatment that is currently nonexistent.