UKY DENTAL COBRE: ORAL INFECTIONS AND HIV RECRUDESCENCE

英国牙科 COBRE：口腔感染和艾滋病毒复发

• 批准号: 6972166
• 负责人: Chifu Brad Huang
• 金额: $ 21.65万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-23 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972166
• 关键词: AIDS therapy; HIV infections; T cell receptor; T lymphocyte; bacteria infection mechanism; biological signal transduction; clinical research; enzyme linked immunosorbent assay; host organism interaction; human immunodeficiency virus 1; intracellular; ligands; macrophage; oral bacteria; periodontitis; polymerase chain reaction

At the end of 2000 it was estimated that over 36 million people were living with the human immunodeficiency virus. The introduction of HAART regimens (Highly Active Antiretroviral Therapy) has significantly modified the course of HIV disease, with longer survival rates and improvement of life quality in HIV-infected individuals. However, complete eradication of HIV infection cannot be achieved with currently available antiretroviral regimens. This primarily results from the establishment of a pool of latently infected CD4+ T cells during the very earliest stages of acute HIV infection that persists with an extremely long half-life. This persistence of HIV-1 within resting CD4+ T cells and macrophages constitutes a major obstacle in the control of HIV-1 infection. The aims are developed to document the capacity and variation in the ability of oral microorganisms to activate HIV(1), to evaluate the ability of oral microorganisms to stimulate resident host cells releasing mediators that would activate HIV-1, and to determine cellular receptors that contribute to this process. The General Hypothesis is that: Oral microorganisms associated with chronic periodontal infections can activate T cells and/or macrophages latently infected with HIV-1, leading to viral recrudescence. Specific Aim a: To determine the capacity of selected oral microorganisms to activate HIV-1 in latently infected T lymphocytes and macrophages. The hypothesis to be tested is: Selected oral microorganisms comprising the oral biofilm in chronic periodontal infections will activate HIV-1 in latently infected T cells and macrophages. We will use model T cell a macrophage cell lines (1G5; BF24, transfected with the HIV promoter) and (J1.1; OM10.1, reactivation of HIV-1) in these studies. Specific Aim 2: To determine the ability of selected oral microorganisms to elicit mediators from resident cell populations that can activate HIV-1 in latently infected T lymphocytes and macrophages. The hypothesis to be tested is: Mediators produced by fibroblasts and epithelial cells stimulated with oral microorganisms will activate HIV in latently infected T cells and macrophages. Specific Aim 3: To determine the target receptors for bacterial and host stimulation of the HIV promoter and HIV reactivation in latently infected T cell and macrophages. The hypothesis to be tested is: There are specific receptors on the latently infected T cells and macrophages that will bind bacterial or host ligands, transducing an intracellular signal leading to activation of HIV. Chronic periodontitis, which represents the clinical presentation of the most ubiquitous infection of mankind, has not be examined for a link altering the persistant viral reservoir in HIV infection. The ability to document that the chronic infection triggering periodontitis, which can also be manifest by peripheral translocation of bacteria, has the capacity to activate latently infected T lymphocytes and/or macrophages could have a substantial impact on understanding oral-systemic disease linkages in HIV infection. The potential that the oral bacterial pathogens could contribute to this inter-cellular signaling would also add to a clearer insight into HAART therapy success/failure, as well as long-term strategies to impact HIV reservoirs. Prevention and intervention for periodontitis are very cost-effective measures, thus, including this strategy into the basic health improvement/maintenance of HIV-infected individuals could have significant public health benefits.

据估计，在2000年底，有超过3600万人患有人类免疫缺陷病毒。 HAART方案的引入（高度活跃的抗逆转录病毒疗法）已显着改变了HIV疾病的进程，其生存率较长和艾滋病毒感染者的生活质量提高。但是，目前可用的抗逆转录病毒方案无法完全消除HIV感染。这主要是由于在急性HIV感染的最早阶段建立了一个潜在感染的CD4+ T细胞池，而急性HIV感染持续存在，其半衰期很长。 HIV-1在静止的CD4+ T细胞和巨噬细胞中的这种持久性构成了控制HIV-1感染的主要障碍。开发目的是记录口服微生物激活HIV的能力的能力和变化（1），评估口服微生物刺激驻留的宿主细胞的能力，从而释放了激活HIV-1的介体，并确定对这一过程有助于此过程的细胞受体的能力。一般假设是：与慢性牙周感染相关的口服微生物可以激活T细胞和/或巨噬细胞。 感染了HIV-1，导致病毒复发。具体目的A：确定选定的口服微生物在潜在感染的T淋巴细胞和巨噬细胞中激活HIV-1的能力。要检验的假设是：选定的口服微生物包括慢性牙周感染中的口服生物膜，将激活潜在感染的T细胞和巨噬细胞中的HIV-1。我们将使用模型T细胞A巨噬细胞系（1G5； BF24，转染） 在这些研究中，使用HIV启动子）和（J1.1; OM10.1，HIV-1的重新激活）。具体目的2：确定选定的口服微生物从居民细胞群中引起介质的能力，这些能力可以激活潜在感染的T淋巴细胞和巨噬细胞中的HIV-1。要检验的假设是：由成纤维细胞和被口服微生物刺激的上皮细胞产生的介质将激活潜在感染的T细胞和巨噬细胞中的HIV。具体目标3：确定潜在感染的T细胞和巨噬细胞中细菌和宿主刺激HIV启动子和HIV重新激活的靶向受体。要测试的假设是：在潜在感染的T细胞和巨噬细胞上有特定的受体结合细菌或宿主配体，导致细胞内信号导致HIV激活。慢性牙周炎代表了人类最普遍的感染的临床表现，尚未检查改变HIV感染中持续性病毒储量的联系。记录慢性感染引发牙周炎的能力，也可以通过细菌的周围易位表现出来，具有激活潜在感染的T淋巴细胞和/或巨噬细胞的能力，可能会对了解HIV感染中的口腔类正性疾病联系产生重大影响。口腔细菌病原体可能有助于这种细胞间信号的潜力也将增加对HAART治疗成功/失败的清晰见解，以及影响HIV储量的长期策略。预防和牙周炎的干预是非常有效的措施，因此，包括此 艾滋病毒感染者的基本健康改善/维护的策略可能具有重大的公共卫生益处。