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（由申请方提供）：HIV疾病中肠道粘膜屏障被破坏，导致微生物产物（如脂多糖（LPS）和细菌DNA）的全身暴露增加。HIV疾病中肠道屏障的紊乱可能源于CD 4 + T细胞的缺失、Th 17辅助细胞的丧失、肠上皮细胞稳态的破坏和体液免疫的降低。尽管有证据表明暴露于微生物制品可能导致HIV疾病的慢性免疫激活，并且也可能在高效抗逆转录病毒治疗（HAART）期间限制CD 4 + T细胞重建中发挥作用，但HIV感染中可渗透肠道屏障的后果尚未完全了解。在这里，我们认为微生物易位也可能在HIV感染的特征性B细胞扰动中发挥重要作用。这些扰动包括多克隆B细胞活化、B细胞功能障碍和记忆B细胞亚群的耗竭。记忆B细胞功能障碍和耗竭是我们提出的研究的焦点，因为我们的初步数据表明，TLR 4配体LPS和HIV病毒体协同诱导体外外周血细胞培养物中的记忆B细胞死亡，增强记忆B细胞离体凋亡和体内LPS的血浆水平，以及降低来自HIV+供体的体内回忆抗体EndoCa B b（针对LPS的中和抗体）的水平。因此，我们假设微生物易位和HIV复制的增加共同驱动外周记忆B耗竭。我们假设，B细胞亚群的某些免疫特征将预测HIV感染中对疫苗接种的抗体反应性降低（特别是对于T细胞非依赖性回忆抗原）。我们建议探索TLR/HIV介导的记忆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细胞依赖性和非依赖性抗原）反应性降低的预测因子。通过确定HIV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），并可能通过恢复保护免受微生物易位的免疫屏障来减缓疾病进展。 公共卫生关系：本研究的目的是探讨外周记忆B细胞丢失和HIV疫苗免疫应答降低的机制。本研究的目标是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），并可能通过恢复保护微生物易位的免疫屏障来减缓疾病进展。