BK Virus: Its role in BLL Causation

描述(由申请人提供)： HIV相关唾液腺疾病(HIVSGD)，也被称为良性淋巴上皮病变(BLL)，是一种艾滋病定义的儿科疾病，高达40%的儿童受到影响。即使在广泛使用高效抗逆转录病毒疗法后，BLL在成人人群中的患病率仍在上升，在发展中国家高达48%的成年人中发现了这种情况。这种毁容的、往往是污名化的疾病严重影响了生活质量(QOL)。在很大一部分受影响的个体中，BLL先于受影响腺体的癌症发展，并易患猖獗的龋齿和进行性牙周病。潜在的致病因素尚未确定，因此尚无有效的治疗方法。这项建议的主题是确定肿瘤诱导的多瘤病毒BK(BKV)与BLL的发展/恶化之间的联系。因此，1)分子流行病学研究应该支持这种联系，2)BKV滴度应该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确认了人类多瘤病毒，BLL中的BK 1)BK病毒基因产物在BLL中持续检测到，2)个体是病毒携带者，3)BKV在他们的口腔分泌物中释放水平升高。我们已经开发了第一个体外BKV唾液腺细胞感染系统，具有生产性的非溶血性感染，反映了疾病，并使BK感染的机制分析成为可能。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。啮齿动物感染同源多瘤病毒会引起类似的唾液腺疾病。综上所述，这些发现导致了以下特定目标的发展，这些目标将探索BKV在唾液腺病理中的作用，并将确定BKV允许性唾液腺感染与BLL之间的联系。根据病因的分子指南，这些目标将通过AIM 1)对BLL进行前瞻性病例对照研究，其中将在腺体和体液(唾液、血清、尿液、血浆、PBL用于病毒区划研究)中分析BKV复制决定因素、抗BKV抗体状况和病毒基因表达。我们将BLL中的唾液功能(静息和刺激流出)和唾液蛋白分泌与BKV滴度相关联。将在BLL组内进行试点随机对照试验。BLL小组将 随机分为BKV靶向抗病毒药物或安慰剂。目的：在一项回顾性纵向研究中，确定BLL是否是儿童原发感染的一种表现。HIV+BLL+患有这种疾病的儿童和与之匹配的暴露于病毒的未感染对照将被评估。目的3)在回顾性纵向研究中，确定成人BLL是否是HAART启动刺激的再激活事件的结果。拟议的分子流行病学研究探索了BKV引起的唾液腺细胞损害的可能性，这些损害影响了对正常腺功能至关重要的过程，并可能支持BKV和BLL之间的因果联系。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。

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.