Periodontitis as a comorbidity in SIV infection and Antiretroviral Therapy

摘要 人类的两种主要口腔疾病是导致龋齿和牙周炎的慢性感染。那里 是牙周炎相关的牙周组织和致病菌改变的特定动力学的证据 在正常人群中，这似乎与衰老和糖尿病不同。然而，目前尚不清楚HIV-1如何 感染和目前使用抗逆转录病毒药物的管理可能会影响微生物组和疾病。也是 目前尚不清楚这种口腔微生物生态学和系统性病毒环境的差异如何与宿主 反应有助于牙周组织的破坏。由于免疫系统的特性 剧目是至关重要的维持一般健康，先天性或后天性干扰发展的正常 免疫功能反映在人群中身体小生境中改变的微生物群中。虽然广泛 在过去的3+十年中，已经获得了关于健康状况下口腔微生物生物膜特征的文献， 牙周炎，这些主要是从患有慢性牙周炎的成年人的横断面研究中报道的。 牙周炎合并HIV-1感染时微生物菌群失调和反应失调的相互作用 抗逆转录病毒治疗（ART）的反应仍然未知。这项建议涉及多学科和 多机构合作的方法来确定的相互作用，慢性口腔感染和 炎症性疾病、牙周炎、SIV感染的病程和特征以及对ART的反应。 该研究将使用结扎诱导牙周炎的非人灵长类动物模型，这是一个完善的模型 口腔感染，炎症和粘膜疾病，在猕猴。实验设计将解决 关于慢性感染和免疫反应失调之间相互作用的具体知识差距， SIV感染引起的免疫学和生物学变化的牙周炎，包括：（i）牙周炎 SIV感染对病毒血症和CD 4+水平的影响;（ii）SIV对口腔微生物组和唾液的影响 和血清反应;和（iii）牙周炎对ART疗效的相互作用。我们的过度假设是 牙周炎和年龄将协同作用，对SIV感染的参数产生负面影响， 影响ART治疗SIV感染的疗效。”我们建议的研究将在三个具体的 目的：具体目的1：描述年龄对老年人口腔微生物组和靶向唾液生物标志物的影响。 健康状况、实验性牙周炎发生的变化以及随后SIV感染的影响。具体 目的2：描述实验性牙周炎和年龄对ART治疗SIV疗效的影响 感染具体目标3：描述严重牙周炎对现有ART疗效的影响 治疗以控制SIV感染。

Abstract The two major oral diseases of mankind are chronic infections that result in dental caries and periodontitis. There is evidence of specific dynamics of alterations in commensal and pathogenic bacteria related to periodontitis within the normal population that appears to differ with aging and in diabetes. It is unclear, however, how HIV-1 infection and current management with antiretroviral drugs may affect the microbiome and disease. It is also unclear how differences in this oral microbial ecology and systemic viral environment together with host responses contribute to the destruction of the periodontium. Since characteristics of the immune system repertoire are critical for maintaining general health, congenital or acquired disruptors of development of normal immune functions are reflected in altered microbiota across body niches within the population. While extensive literature has been acquired over the last 3+ decades on the features of the oral microbial biofilms in health and periodontitis, these have primarily been reported from cross-sectional studies in adults with chronic periodontitis. The interaction of a microbial dybiosis and dysregulated response in periodontitis coincident with HIV-1 infection and response to antiretroviral therapy (ART) remains unknown. This proposal engages a multi-disciplinary and multi-institutional collaborative approach for the determination of the interaction of the chronic oral infection and inflammatory disease, periodontitis, with the course and characteristics of SIV infections and response to ART. The study will use a nonhuman primate model of ligature-induced periodontitis, which is a well-established model of oral infection, inflammation, and mucosal disease, in Macaca mulatta. The experimental design will address specific knowledge gaps about the interaction of the chronic infection and dysregulated immune responses of periodontitis with the immunological and biologic changes occurring with SIV infection, including: (i) Periodontitis effects on the viremia and CD4+ levels from SIV infection; (ii) SIV effects on the oral microbiome and salivary and serum responses; and (iii) Interaction of periodontitis on ART efficacy. Our over-arching hypothesis is that “Periodontitis and age will synergize to negatively impact parameters of SIV infection and will deleteriously affect the efficacy of ART in managing the SIV infection.” Our proposed studies will be examined in three Specific Aims: Specific Aim 1: To delineate age effects on the oral microbiome and targeted salivary biomarkers in health, changes that occur with experimental periodontitis, and impact of a subsequent SIV infection. Specific Aim 2: To delineate the effect of experimental periodontitis and age on the efficacy of ART treatment for an SIV infection. Specific Aim 3: To delineate the effect of severe periodontitis on the efficacy of existing ART treatment to control an SIV infection.