Synergistic effect of HIV virions and bacterial LPS on memory B cell apoptosis

HIV病毒体和细菌LPS对记忆B细胞凋亡的协同作用

• 批准号: 8210255
• 负责人: Wei Jiang
• 金额: $ 31.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210255
• 关键词: Antibodies; Antibody Formation; Antigens; Apoptosis; Apoptotic; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial DNA; Blood Cells; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Characteristics; Chronic; Cross-Sectional Studies; Data; Disease; Disease Progression; Enterocytes; Exposure to; Flow Cytometry; Functional disorder; Goals; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Hepatitis B Vaccines; Hepatitis B Virus; Highly Active Antiretroviral Therapy; Homeostasis; Humoral Immunities; Immune; Immune response; Immunologics; In Vitro; Ligands; Lipopolysaccharides; Measures; Mediating; Mediator of activation protein; Memory; Memory B-Lymphocyte; Modeling; Molecular; Mononuclear; Opportunistic Infections; Pathogenesis; Pathway interactions; Peripheral; Plasma; Play; Polyvalent pneumococcal vaccine; RNA; Receptors, Antigen, B-Cell; Role; Sorting - Cell Movement; Streptococcus pneumoniae; T-Lymphocyte; TLR4 gene; Testing; Vaccination; Vaccines; Viremia; Virion; cohort; immune activation; improved; in vivo; indexing; microbial; neutralizing antibody; reconstitution; response; stem; therapy design

DESCRIPTION (provided by applicant): The gut mucosal barrier is disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Lipopolysaccharide (LPS) and bacterial DNA. Perturbations in the gut barrier in HIV disease may stem from deletion of CD4+ T cells, loss of Th17 helper cells, disruption of enterocyte homeostasis and diminished humoral immunity. The consequences of a permeable gut barrier in HIV infection are not fully understood, although there is evidence that exposure to microbial products could contribute to chronic immune activation in HIV disease and may also play a role in limiting CD4+ T cell reconstitution during highly active antiretroviral therapy (HAART). Here, we consider the possibility that microbial translocation also could play an important role in B cell perturbations that are characteristic of HIV infection. These perturbations include polyclonal B cell activation, B cell dysfunction and depletion of the memory B cell subset. Memory B cell dysfunction and depletion are the focus of our proposed studies as our preliminary data demonstrate that the TLR4 ligand LPS, and HIV virions cooperate to induce memory B cell death in peripheral blood cell cultures in vitro, enhanced memory B cell apoptosis ex vivo and plasma levels of LPS in vivo, and decreased level of recall antibody EndoCab (neutralizing antibody against LPS) in vivo from HIV+ donors. Therefore, we hypothesize that heightened microbial translocation and HIV replication collaborate to drive peripheral memory B depletion. We hypothesize that certain immune signatures of B cell subsets will predict reduced antibody responsiveness to vaccination (especially for T cell independent recall antigens) in HIV infection. We propose to explore the mechanisms responsible for TLR/HIV-mediated memory B cell death and to investigate in vivo correlates of these findings including identifying the predictors for reduced vaccine (both T cell dependent and independent antigens) responsiveness in HIV infection. By determining the mechanisms of B cell depletion and perturbations in HIV disease, we may be better able to design interventions that will potentially improve immune responses to vaccines, reduce selected opportunistic infections (e.g. pneumococcus) and perhaps slow disease progression by restoring the immunologic barrier that protects against microbial translocation. PUBLIC HEALTH RELEVANCE: The purpose of the present study is to explore the mechanisms of peripheral memory B cell loss and reduced vaccine responsiveness in HIV infection. The goals of the present study are better to design interventions that will potentially improve immune responses to vaccines, reduce selected opportunistic infections (e.g. pneumococcus) and perhaps slow disease progression by restoring the immunologic barrier that protects against microbial translocation.

描述（由申请人提供）：在HIV疾病中，肠道粘膜屏障被破坏，导致系统暴露于微生物产物如脂多糖（LPS）和细菌DNA增加。HIV疾病中肠道屏障的紊乱可能源于CD4+ T细胞的缺失、Th17辅助细胞的缺失、肠细胞稳态的破坏和体液免疫的减弱。尽管有证据表明，暴露于微生物产品可能导致艾滋病毒疾病的慢性免疫激活，并且可能在高活性抗逆转录病毒治疗（HAART）期间限制CD4+ T细胞重构中发挥作用，但可渗透肠道屏障在艾滋病毒感染中的后果尚不完全清楚。在这里，我们考虑微生物易位也可能在B细胞扰动中发挥重要作用，这是HIV感染的特征。这些扰动包括多克隆B细胞激活、B细胞功能障碍和记忆B细胞亚群的耗竭。我们提出的研究重点是记忆B细胞功能障碍和耗竭，因为我们的初步数据表明，TLR4配体LPS和HIV病毒颗粒共同诱导体外外周血培养的记忆B细胞死亡，增强体外记忆B细胞凋亡和体内血浆LPS水平，降低体内HIV+供者的回忆抗体EndoCab（对抗LPS的中和抗体）水平。因此，我们假设微生物易位和HIV复制加剧共同驱动外周记忆B耗竭。我们假设，在HIV感染中，B细胞亚群的某些免疫特征将预测抗体对疫苗应答性的降低（特别是对T细胞独立的召回抗原）。我们建议探索TLR/HIV介导的记忆性B细胞死亡的机制，并研究这些发现的体内相关性，包括确定HIV感染中疫苗（T细胞依赖性和独立抗原）反应性降低的预测因子。通过确定艾滋病毒疾病中B细胞耗竭和扰动的机制，我们可能能够更好地设计干预措施，这些干预措施可能会改善对疫苗的免疫反应，减少选定的机会性感染（例如肺炎球菌），并可能通过恢复防止微生物易位的免疫屏障来减缓疾病进展。