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.

2000年底，估计有3600万人携带人类免疫缺陷病毒。HAART方案(高效抗逆转录病毒疗法)的引入显著改变了艾滋病毒的病程，提高了艾滋病毒感染者的存活率和生活质量。然而，用现有的抗逆转录病毒疗法不能完全根除艾滋病毒感染。这主要是由于在急性艾滋病毒感染的最早阶段建立了潜伏感染的CD4+T细胞池，并持续了极长的半衰期。HIV-1在静息的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。其目的是记录口腔微生物激活艾滋病毒的能力和变化(1)，评估口腔微生物刺激常驻宿主细胞释放将激活艾滋病毒-1的介体的能力，并确定有助于这一过程的细胞受体。一般假设是：与慢性牙周感染相关的口腔微生物可以潜伏地激活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：确定选定的口腔微生物在潜伏感染的T淋巴细胞和巨噬细胞中激活HIV-1的能力。需要检验的假设是：在慢性牙周感染中，由口腔生物膜组成的选定口腔微生物将激活潜伏感染的T细胞和巨噬细胞中的HIV-1。我们将用模型T细胞a巨噬细胞系(1G5；BF24，转基因) 与HIV启动子)和(J1.1；OM10.1，HIV-1的重新激活)在这些研究中。具体目标2：确定选定的口腔微生物从常驻细胞群中诱导媒介的能力，这些媒介可以激活潜伏感染的T淋巴细胞和巨噬细胞中的HIV-1。需要检验的假设是：口腔微生物刺激的成纤维细胞和上皮细胞产生的介质将激活潜伏感染的T细胞和巨噬细胞中的艾滋病毒。具体目标3：确定细菌和宿主刺激HIV启动子和潜伏感染的T细胞和巨噬细胞重新激活HIV的靶受体。需要检验的假设是：潜伏感染的T细胞和巨噬细胞上有特定的受体，它们将与细菌或宿主配体结合，传递导致HIV激活的细胞内信号。慢性牙周炎代表着人类最普遍的感染的临床表现，尚未被检查是否与改变艾滋病毒感染中的持久病毒储备库有关。证明引发牙周炎的慢性感染具有激活潜伏感染的T淋巴细胞和/或巨噬细胞的能力，这一点也可通过细菌的外周移位表现出来，这可能对理解口腔-全身疾病与艾滋病毒感染的联系具有重大影响。口腔细菌病原体可能有助于这种细胞间信号传递，这也将有助于更清楚地了解HAART治疗的成功/失败，以及影响艾滋病毒宿主的长期策略。预防和干预牙周炎是非常具有成本效益的措施，因此，包括 将这一战略纳入艾滋病毒感染者的基本健康改善/维持，可能会对公共健康产生重大益处。