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.

项目概要/摘要 HIV感染导致肠道相关淋巴组织的变化，但很少有研究评估 在口腔中是否发生类似的粘膜免疫功能障碍。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方面的重要性，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发病机制 炎症仍然不明确。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HIV的常用动物模型（非人灵长类动物的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）是一种嗜T细胞慢病毒 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， 艾滋病与此相关的建议，与艾滋病病毒感染类似，牙周和口腔炎症也会发生 在大多数FIV感染的动物中。我们的初步研究表明，家猫感染FIV是 与以下相关：（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，易于管理的 在猕猴中对SIV有效的cART方案在体外强烈抑制FIV生长。开发一个好的- 耐受的、有效的cART是开发FIV体内模型用于后续研究的重要下一步。 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， 在存在和不存在FIV病毒复制的情况下发生的逐步病理。我们将监测临床状态，口服 微生物群、局部和全身病毒负荷以及在存在和不存在 一种新的cART疗法目的1将评估cART在控制口腔病毒复制和后续治疗中的作用。 对急性和亚急性感染期间口腔微生物组和局部炎症的影响。目标2将适用因果关系 模型（结构方程模型）和模型选择，以确定直接和间接的机械基础， 在存在和不存在cART的情况下FIV诱导的牙周病。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， 将我们的研究结果转化为基于假设的方法，用于HIV相关口腔疾病的新治疗干预。 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全身免疫缺陷 和感染