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: 7610647
• 负责人: Chifu Brad Huang
• 金额: $ 20.73万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610647
• 关键词: Acute; Anti-Retroviral Agents; Automobile Driving; Bacteria; CD4 Positive T Lymphocytes; Cell Line; Cells; Characteristics; Chloramphenicol O-Acetyltransferase; Chronic; Coculture Techniques; Computer Retrieval of Information on Scientific Projects Database; Data; Dendritic Cells; Dental; Disease; Dose; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Funding; Genes; Gingiva; Grant; HIV; HIV Infections; HIV-1; Half-Life; Highly Active Antiretroviral Therapy; Human; Immune; Individual; Infection; Institution; Measures; Modeling; Oral; Outcome; Patients; Periodontitis; Quality of life; Reaction; Recrudescences; Research; Research Personnel; Resources; Risk; Source; Specificity; Staging; Survival Rate; System; T-Lymphocyte; Time; Treatment Protocols; United States National Institutes of Health; Variant; macrophage; mast cell; microbial; oral bacteria; oral infection; promoter; research study; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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, macrophages, and other host cells (eg. dendritic cells, mast cells) during the very earliest stages of acute HIV infection that persists with an extremely long half-life. This persistence of HIV-1 within various host immune cells, including macrophages constitutes a major obstacle in the control of HIV-1 infection. We are using model T cell and macrophage systems to evaluate the capacity of the oral microbial challenges to reactivate HIV. Our initial studies have used the BF24 cell line, a human macrophage transfected with the HIV LTR promoter driving a chloramphenicol acetyltransferase (CAT) gene. Specific Aim 1 was to examine the alteration of these cells were challenged with oral bacteria (Pg, Sm, Cr, Fn) or sonicates to assess variations in HIV promoter activation related to species, dose, and time. We also evaluated the ability of a polymicrobial challenge to synergize in this activation. The outcome was measured using a CAT ELISA. Differences were noted in the ability of the various oral bacteria and bacterial sonicates to activate HIV, supporting that the characteristics of oral infection in periodontitis patients could variably impact reactivation of HIV. We also noted that a polybacterial challenge of the BF24 cells demonstrated an additive reactivation when compared to either bacterium alone. Specific Aim 2 focuses on the ability of host induced molecules to reactivate HIV. In these studies, we have challenged human gingival fibroblast (HGF) cultures with various bacterial sonicates. The resulting supernatants were then used to stimulate HIV reactivation in the BF24 cells. The findings indicated a dose and time responsiveness for the HGF supernatants to stimulate the BF24 cells. However, these reactions appeared substantially less that direct bacterial stimulation of the macrophages. Finally, we have initiated some co-culture experiments in which the HGF, macrophages and bacterial challenge take place in the same milieu. Initial results suggest that factors in these cultures may actually modulate the ability to activate the HIV promoter. Thus, the data demonstrate that oral bacteria have the capacity to activate HIV in latently infected macrophages. There appeared some specificity to the magnitude of this activation and a polybacterial challenge of these infected cells can enhance HIV reactivation. The results suggest chronic oral infections provide a risk to treatment success in HIV infected patients.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 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感染的最早阶段中建立了一个潜在感染的CD4+ T细胞，巨噬细胞和其他宿主细胞（例如树突状细胞，肥大细胞）的池，这些细胞具有极长的半衰期。 HIV-1在各种宿主免疫细胞中的这种持久性（包括巨噬细胞）构成了控制HIV-1感染的主要障碍。 我们正在使用模型T细胞和巨噬细胞系统来评估口腔微生物挑战重新激活HIV的能力。 我们的最初研究使用了BF24细胞系，BF24细胞系是一种用HIV LTR启动子驱动氯霉素乙酰基转移酶（CAT）基因转染的人类巨噬细胞。具体目的1是检查这些细胞的改变被口服细菌（PG，SM，CR，FN）或超声酸盐挑战，以评估与物种，剂量和时间有关的HIV启动子激活的变化。我们还评估了多数型挑战在这种激活中协同作用的能力。使用CAT ELISA测量结果。注意到各种口腔细菌和细菌超声激活HIV的能力的差异，支持牙周炎患者口腔感染的特征可能会多样化影响HIV的重新激活。 我们还注意到，与单独的两种细菌相比，BF24细胞的多细菌挑战表现出添加剂的重新激活。 特定的目标2着重于宿主诱导分子重新激活HIV的能力。 在这些研究中，我们挑战了具有各种细菌超声酸盐的人类牙龈成纤维细胞（HGF）培养物。 然后使用所得的上清液刺激BF24细胞中的HIV重新激活。 研究结果表明，HGF上清液刺激BF24细胞的剂量和时间响应能力。 然而，这些反应似乎少于直接对巨噬细胞的细菌刺激。 最后，我们启动了一些共培养实验，其中HGF，巨噬细胞和细菌挑战在同一环境中发生。 最初的结果表明，这些培养物中的因素实际上可能调节激活HIV启动子的能力。 因此，数据表明，口腔细菌具有在潜在感染的巨噬细胞中激活HIV的能力。似乎对这种激活的大小有一定的特异性，这些感染细胞的多分裂挑战可以增强HIV的重生。结果表明，慢性口腔感染为HIV感染患者提供了治疗成功的风险。