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

基本信息

批准号：
10228085
负责人：
SUE VANDEWOUDE
金额：
$ 18.96万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-03 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228085
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 Lentivirus 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 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 opportunistic pathogen oral HIV oral condition oral microbial community oral microbiome programs response simian human immunodeficiency virus systemic inflammatory response

项目摘要

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.

程序摘要 /摘要 HIV感染导致对肠道相关淋巴组织的有据可查的变化，但很少有研究评估口腔中是否发生类似的粘膜免疫功能障碍。而且，尽管有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社区和导致免疫缺陷引起的牙周炎和全身性的机制炎症的定义仍然很差。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HIV的常用动物模型（非人类灵长类动物的SIV/SHIV感染和HIV感染人性化小鼠）不能可靠地导致口腔疾病。猫免疫缺陷病毒（FIV）是T细胞热带慢病毒这会引起其自然宿主的帮助，并导致免疫功能障碍和机会性感染类似艾滋病毒。与该提案有关，与HIV感染相似，牙周和口腔炎症性疾病发生在大多数FIV感染的动物中。我们的初步研究表明，家猫的FIV感染是与：（1）口腔失调有关，在FIV相关牙周炎期间，微生物多样性的显着丧失；和（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，很容易管理猕猴中针对SIV的CART方案有效地在体外抑制了FIV的生长。发展耐受性，有效的购物车是开发FIV的体内模型的重要下一步，用于跟进研究艾滋病毒疾病。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。我们将监控临床状态，口服在存在和不存在的情况下，微生物群，局部和全身病毒负担以及全身治疗期间的免疫特征一种新颖的购物车疗法。 AIM 1将评估购物车在控制口腔病毒复制和随后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。 AIM 2将适用因果关系建模（结构方程建模）和模型选择，以确定在存在和不存在CART的情况下，FIV诱导的牙周疾病。我们组建了一支经验丰富的团队研究人员进行拟议的实验和建模，并将与HIV口腔疾病专家合作将我们的发现转化为基于假设的方法，用于针对HIV相关的口服的新治疗干预措施疾病。此外，我们的工作将询问与口腔病毒复制有关的局部和全身免疫缺陷和感染。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Combination Antiretroviral Therapy and Immunophenotype of Feline Immunodeficiency Virus.

DOI：
10.3390/v15040822
发表时间：
2023-03-24
期刊：
Viruses
影响因子：
0
作者：
Kim J;Behzadi ES;Nehring M;Carver S;Cowan SR;Conry MK;Rawlinson JE;VandeWoude S;Miller CA
通讯作者：
Miller CA