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

基本信息

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
项目类别：
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

项目摘要

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，肠粘膜屏障被破坏，导致全身暴露于脂多糖 (LPS) 和细菌 DNA 等微生物产物的增加。 HIV 疾病中肠道屏障的扰动可能源于 CD4+ T 细胞的缺失、Th17 辅助细胞的丧失、肠上皮细胞稳态的破坏和体液免疫的减弱。尽管有证据表明，接触微生物产品可能导致 HIV 疾病的慢性免疫激活，并且还可能在高效抗逆转录病毒治疗期间限制 CD4+ T 细胞重建，但可渗透性肠道屏障在 HIV 感染中的后果尚不完全清楚。（HAART）。在这里，我们考虑微生物易位也可能在 HIV 感染特征的 B 细胞扰动中发挥重要作用的可能性。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。记忆 B 细胞功能障碍和耗竭是我们提出的研究的重点，因为我们的初步数据表明，TLR4 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，增强离体记忆 B 细胞凋亡，并增强记忆 B 细胞的凋亡。 HIV+ 供体体内 LPS 血浆水平，以及体内召回抗体 EndoCab（针对 LPS 的中和抗体）水平降低。因此，我们假设微生物易位增强和 HIV 复制共同导致外周记忆 B 耗竭。我们假设 B 细胞亚群的某些免疫特征将预测 HIV 感染中抗体对疫苗接种的反应性降低（特别是 T 细胞独立回忆抗原）。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 细胞依赖性和独立抗原）反应性降低的预测因素。通过确定 HIV 疾病中 B 细胞耗竭和扰动的机制，我们也许能够更好地设计干预措施，从而改善对疫苗的免疫反应，减少特定的机会性感染（例如肺炎球菌），并可能通过恢复免疫屏障来减缓疾病进展。防止微生物移位。公共健康相关性：本研究的目的是探讨 HIV 感染中外周记忆 B 细胞丢失和疫苗反应降低的机制。本研究的目标是更好地设计干预措施，潜在地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。