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）：肠粘膜屏障在HIV疾病中受到破坏，导致全身性接触微生物产物（如脂多糖）（LPS）和细菌DNA。 HIV疾病中肠道障碍的扰动可能源于CD4+ T细胞的缺失，Th17辅助细胞的丧失，肠肠上稳态的破坏和体液免疫的降低。尽管有证据表明，微生物产物的暴露可能导致HIV疾病中的慢性免疫激活，并且在限制高度活跃的抗逆转录病毒治疗（HAART）中可能有助于CD4+ T细胞重构，但也可能在限制CD4+ T细胞重构中发挥作用。在这里，我们认为微生物易位也可能在HIV感染的特征的B细胞扰动中起重要作用。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细胞子集的耗竭。记忆B细胞功能障碍和消耗是我们提出的研究的重点来自HIV+供体的体内。因此，我们假设增强的微生物易位和HIV复制协作以驱动周围内存B耗竭。我们假设B细胞亚群的某些免疫特征可以预测HIV感染中对疫苗接种的抗体反应降低（尤其是T细胞独立召回抗原）。我们建议探索负责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，包括鉴定HIV感染中降低疫苗（T细胞依赖性和独立抗原）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，我们可能会更好地设计干预措施，从而有可能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）（例如肺炎球菌），并可能通过恢复免疫障碍，以防止微生物转化。公共卫生相关性：本研究的目的是探索周围记忆B细胞损失的机制，并降低HIV感染中的疫苗反应能力。本研究的目标是设计干预措施，该干预措施将有可能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），并通过恢复保护免受微生物易位的免疫障碍来恢复疾病的进展缓慢。