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

描述(申请人提供)：在HIV疾病中，肠道粘膜屏障被破坏，导致全身暴露于微生物产品，如脂多糖(LPS)和细菌DNA。HIV疾病中肠道屏障的紊乱可能源于CD4+T细胞的缺失，Th17辅助细胞的丧失，肠细胞动态平衡的破坏和体液免疫的降低。尽管有证据表明，接触微生物产品可能有助于HIV疾病的慢性免疫激活，并可能在高效抗逆转录病毒治疗(HAART)期间限制CD4+T细胞的重建，但通透性肠道屏障在HIV感染中的后果尚不完全清楚。在这里，我们考虑了微生物易位在B细胞紊乱中发挥重要作用的可能性，B细胞紊乱是HIV感染的特征。这些干扰包括多克隆B细胞激活、B细胞功能障碍和记忆B细胞亚群的耗尽。记忆B细胞功能障碍和耗竭是我们建议的研究重点，因为我们的初步数据表明，TLR4配体和HIV病毒粒子在体外协同诱导外周血细胞培养中的记忆B细胞死亡，在体外增加记忆B细胞的凋亡和体内血浆内毒素水平，并降低体内HIV+捐赠者的Recall抗体EndoCab(抗内毒素中和抗体)水平。因此，我们假设，微生物移位和HIV复制的增加共同推动了外周记忆B的耗尽。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(特别是对T细胞非依赖召回抗原)的抗体反应性降低。我们建议探索TLR/HIV介导的记忆B细胞死亡的机制，并调查这些发现的体内相关性，包括确定HIV感染中疫苗(T细胞依赖和独立抗原)反应性降低的预测因子。通过确定HIV疾病中B细胞耗尽和扰动的机制，我们可能能够更好地设计干预措施，潜在地改善对疫苗的免疫反应，减少特定的机会性感染(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。

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.