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

抗逆转录病毒治疗对 FIV 动物模型口腔稳态的影响

• 批准号: 10082980
• 负责人: SUE VANDEWOUDE
• 金额: $ 24.06万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082980
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Animal Model; Animals; Bacterial Translocation; Biological Models; Chronic; Chronic Gingivitis; Clinical; Clinical Trials; Communities; Controlled Study; Data; Data Set; Development; Diet; Disease; Dysplasia; Environment; Equation; Exposure to; Family Felidae; Feline Immunodeficiency Virus; Felis catus; Formulation; Future; Gastrointestinal tract structure; Gingivitis; Goals; Growth; Gut associated lymphoid tissue; HIV; HIV Infections; Health; Homeostasis; Human; Immune; Immune System Diseases; Immunologic Deficiency Syndromes; Immunologics; In Vitro; Infection; Inflammation; Inflammatory; Laboratories; Lymphoid Tissue; Macaca; Microbiology; Modeling; Molecular; Monitor; Mouth Diseases; Mucous Membrane; Opportunistic Infections; Oral; Oral Manifestations; Oral Pathology; Oral cavity; Oral mucous membrane structure; Outcome; Pathology; Pathway interactions; Patients; Periodontal Diseases; Periodontitis; Personal Satisfaction; Physiological; Protocols documentation; Publishing; Reporting; Research Personnel; Risk; Role; SIV; Salivary; Sampling; Statistical Models; Structure; Subfamily lentivirinae; Systemic disease; T-Lymphocyte; Tenofovir; Testing; Therapeutic; Therapeutic Intervention; TimeLine; Translating; Variant; Viral; Viral Load result; Virus Diseases; Virus Replication; Work; analog; antiretroviral therapy; base; biosecurity; causal model; cytokine; dysbiosis; emtricitabine; experience; experimental study; germ free condition; humanized SCID mouse; humanized mouse; immune activation; immune function; in vivo Model; mathematical model; microbial; microbial community; microbiome; microbiome analysis; microbiome research; mouse model; nonhuman primate; novel; novel therapeutic intervention; oral HIV; oral condition; oral microbial community; oral microbiome; pathogen; programs; response; simian human immunodeficiency virus

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.

计划摘要/摘要 HIV 感染会导致肠道相关淋巴组织发生变化，但很少有研究对其进行评估 口腔是否也出现类似的粘膜免疫功能障碍。此外，尽管越来越多的证据表明 微生物组在维持健康和局部稳态中的重要性、艾滋病毒对口腔微生物的影响 免疫缺陷引起的牙周炎和系统性牙周炎的群落和机制 炎症的定义仍然不明确。由于缺乏合适的动物，对这些现象的研究受到了阻碍 模型，作为常用的 HIV 动物模型（非人类灵长类动物的 SIV/SHIV 感染和 人源化小鼠）不会可靠地导致口腔疾病。猫免疫缺陷病毒 (FIV) 是一种 T 细胞嗜性慢病毒 在其自然宿主中引起艾滋病，并导致免疫功能障碍和机会性感染，类似于 艾滋病毒/艾滋病。与该提案相关，与艾滋病毒感染类似，牙周和口腔炎症性疾病也会发生 在大多数感染 FIV 的动物中。我们的初步研究表明，家猫的 FIV 感染是 与以下因素相关：（1）口腔生态失调，在 FIV 相关牙周炎期间微生物多样性显着丧失；并且，(2) 即使没有 FIV 临床口腔疾病，唾液细胞因子水平也会发生变化。此外，一个易于管理的 cART 方案对猕猴中的 SIV 有效，并在体外强烈抑制 FIV 生长。发展一个良好的 耐受的、有效的 cART 是开发 FIV 体内模型以进行后续研究的重要下一步 艾滋病毒疾病。因此，我们建议通过评估来验证 FIV 作为 HIV 相关口腔疾病的相关模型 在存在和不存在 FIV 病毒复制的情况下发生的逐步病理学。我们将监测临床状态、口腔状况 在存在或不存在的情况下，全身治疗期间的微生物群、局部和全身病毒负荷以及免疫特征 一种新颖的 cART 疗法。目标 1 将评估 cART 在控制口腔病毒复制和随后的治疗方面的影响 急性和亚急性感染期间对口腔微生物组和局部炎症的影响。目标 2 将应用因果关系 建模（结构方程模型）和模型选择以确定直接和间接机制基础 在存在和不存在 cART 的情况下 FIV 诱发的牙周病。我们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，用于艾滋病毒相关口腔的新治疗干预措施 疾病。我们的进一步工作将探讨与口腔病毒复制相关的局部和全身免疫缺陷 和感染。