Impacts of antiretroviral therapy on oral cavity homeostasis in an FIV animal model

计划摘要/摘要 HIV感染会导致肠道相关淋巴组织的变化，但很少有研究对此进行评估 口腔内是否出现类似的黏膜免疫功能障碍。此外，尽管有越来越多的证据表明 微生物群在维持健康和局部动态平衡方面的重要性，艾滋病毒对口腔微生物的影响 免疫缺乏性牙周炎和系统性牙周炎的社区和机制 炎症的定义仍然不明确。由于缺乏合适的动物，对这些现象的研究一直受到阻碍 模型，作为常用的艾滋病毒动物模型(非人灵长类SIV/SIV感染和#年艾滋病毒感染 人源化的小鼠)不会可靠地导致口腔疾病。猫免疫缺陷病毒(FIV)是一种嗜T细胞的慢病毒 这会在其自然宿主中引起艾滋病，并导致免疫功能障碍和类似于 艾滋病毒-艾滋病。与这一建议相关，与艾滋病毒感染类似，牙周炎和口腔炎症性疾病会发生 在大多数感染FIV的动物身上。我们的初步研究表明，家猫的FIV感染 与：(1)口腔微生物失调，在与FIV相关的牙周炎期间微生物多样性显著丧失；以及，(2) 唾液细胞因子水平的变化，即使在没有FIV临床口腔疾病的情况下。此外，一种易于管理的 CART方案对猕猴SIV有效，体外强烈抑制FIV生长。一口井的开发-- 耐受、有效的CART是为后续研究开发FIV活体模型的重要下一步 艾滋病。因此，我们建议通过评估FIV作为HIV相关口腔疾病的相关模型来验证 在存在和不存在FIV病毒复制的情况下发生的阶段性病理。我们将监测临床状态，口头 有无全身治疗期间的微生物区系、局部和全身病毒负荷以及免疫状况 一种新颖的购物车疗法。目标1将评估CART在控制口腔病毒复制和随后的 急性和亚急性感染对口腔微生物群和局部炎症的影响。目标2将适用因果关系 建模(结构方程建模)和模型选择，以确定直接和间接的机理基础 FIV诱导的牙周病在CART存在和不存在的情况下。我们已经组建了一支经验丰富的团队 研究人员将进行拟议的实验和建模，并将与艾滋病毒口腔疾病专家合作 将我们的发现转化为基于假设的方法，用于HIV相关口腔的新治疗干预 疾病。进一步，我们的工作将询问与口腔病毒复制相关的局部和系统免疫缺陷 和感染。

Program Summary / Abstract HIV infection results in well-documented changes to gut-associated lymphoid tissue, but few studies have evaluated whether similar mucosal immunological dysfunction occurs in the oral cavity. Moreover, despite growing evidence of the importance of the microbiome in maintaining health and local homeostasis, the impacts of HIV on oral microbial communities and the mechanisms contributing to immunodeficiency-induced periodontitis and systemic inflammation remain poorly defined. Studies of these phenomena have been hampered by lack of a suitable animal model, as commonly used animal models for HIV (SIV/SHIV infections of non-human primates and HIV infections in humanized mice) do not reliably result in oral disease. Feline immunodeficiency virus (FIV) is a T cell tropic lentivirus that causes AIDS in its natural host, and results in immunological dysfunctions and opportunistic infections similar to HIV-AIDS. Relevant to this proposal, and similar to HIV infections, periodontal and oral inflammatory disease occurs in the majority of FIV-infected animals. Our preliminary studies demonstrate that FIV infection of domestic cats is associated with: (1) oral dysbiosis, with a marked loss of microbial diversity during FIV-associated periodontitis; and, (2) changes in salivary cytokine levels, even in the absence of FIV clinical oral disease. Furthermore, an easily administered cART protocol efficacious against SIV in macaques strongly inhibits FIV growth in vitro. Development of a well- tolerated, effective cART is an important next step in developing the FIV in vivo model for follow-on studies of HIV disease. We therefore propose to validate FIV as a relevant model for HIV-associated oral disease by assessing stepwise pathology that occurs in the presence and absence of FIV viral replication. We will monitor clinical status, oral microbiota, local and systemic viral burden, and immune profile during systemic treatment in the presence and absence of a novel cART therapy. Aim 1 will assess the impact of cART in controlling oral cavity viral replication and subsequent impacts on oral microbiome and local inflammation during acute and subacute infection. Aim 2 will apply causal modeling (Structural Equation Modeling) and model selection to determine the direct and indirect mechanistic basis of FIV-induced periodontal disease in the presence and absence of cART. We have assembled an experienced team of investigators to conduct the proposed experiments and modeling, and will work with experts in HIV oral disease to translate our findings into hypothesis-based approaches for new therapeutic interventions for HIV-associated oral disease. Further our work will interrogate local and systemic immune deficits related to oral cavity viral replication and infection.