Investigate the mechanism of autoreactive B cell-mediated immunological failure despite virologic suppression in HIV-infected individuals on antiretroviral therapy
研究尽管接受抗逆转录病毒治疗的 HIV 感染者出现病毒学抑制,但自身反应性 B 细胞介导的免疫失败的机制
基本信息
- 批准号:10368232
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccountingAffinityAntibodiesAntibody-Producing CellsAntigensAreaAutoantibodiesAvidityB-Cell Antigen ReceptorB-Lymphocyte EpitopesB-LymphocytesB-cell receptor repertoire sequencingBindingBiochemicalBlood specimenCD4 AntigensCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell CountCell DeathCell LineCell physiologyCellsCessation of lifeCharacteristicsClinicalCommon EpitopeCryopreservationData SetDevelopmentDisease ProgressionEpitope MappingEpitopesFailureFibrosisFlow CytometryGene ExpressionGenesGenomicsGoalsHIVHIV Envelope Protein gp120HIV InfectionsHIV SeropositivityHospitalsImmuneImmunoglobulin GImmunologicsIn VitroIndividualInflammationInfluenzaInterventionInvestigationLightLymphaticMediatingMessenger RNAMolecularMonoclonal AntibodiesMorbidity - disease ratePathogenesisPathologicPeripheral Blood Mononuclear CellPersonsPlasmaPlayPopulationProductionPropertyPublic HealthPublishingRecoveryReportingRoleSignal PathwaySignal TransductionSpecificitySurfaceT cell reconstitutionT-Cell ActivationT-Cell DepletionTLR2 geneTLR4 geneTestingTherapeuticThymus GlandVeteransWorkantibody-dependent cell cytotoxicityantigen bindingantiretroviral therapyautoreactive B cellhigh riskimmune activationinhibitorlatent HIV reservoirlatent infectionmortalitypreventrecruittargeted treatmenttherapeutic targettranscriptome sequencing
项目摘要
In HIV infection, circulating CD4+ T cell counts predict disease progression. Even under long-term suppressive
antiretroviral therapy (ART), up to 25% of virologically suppressed people living with HIV (PLWH) fail to restore
CD4+ T cell counts to the levels similar to those in healthy controls, and increased morbidity and mortality have
been demonstrated in these immune non-responders. We were the first group to report that anti-CD4 IgGs
mediate CD4+ T cell death and play a role in poor immune recovery under ART. While the pathogenesis is likely
multifactorial, such as thymic and lymphatic fibrosis, systemic immune activation, and inflammation, our
proposed pathologic anti-CD4 IgG-mediated CD4+ T cell depletion provides a unique mechanism for targeting
CD4+ T cells specifically. In the current study, we will investigate the molecular mechanisms of pathologic anti-
CD4 IgGs and anti-CD4 autoreactive B cells from immune non-responders and identify the therapeutic targets
to prevent anti-CD4 IgG-mediated pathogenesis together with traditional ART to increase immune recovery and
reduce complications, morbidity and mortality in HIV+ Veterans and non-Veterans.
AIM 1. Determine the pathologic activities of anti-CD4 IgGs on CD4+ T cell activation and function and HIV
latency through the CD4 receptor signaling pathway in HIV+ immune non-responders.
AIM 2. Determine the B cell receptor characteristics and gene expression landscape of anti-CD4 autoantibody-
producing B cells from HIV+ immune non-responders.
AIM 3. Determine the biochemical properties and shared antigen binding epitopes of pathologic anti-CD4
monoclonal IgGs in HIV+ immune non-responders.
This line of investigation possesses great therapeutic potential for Veteran and non-Veteran HIV-positive
individuals presenting with poor CD4+ T cell recovery, a population with particularly high risk for morbidity and
mortality and thus an area of public health importance.
在HIV感染中,循环CD 4 + T细胞计数可预测疾病进展。即使在长期的压抑下,
抗逆转录病毒疗法(ART),高达25%的病毒学抑制的艾滋病毒感染者(PLWH)未能恢复
CD 4 + T细胞计数水平与健康对照组相似,发病率和死亡率增加,
在这些免疫无应答者中得到证实。我们是第一个报告抗CD 4 IgG的小组
介导CD 4 + T细胞死亡,并在ART下免疫恢复不良中发挥作用。虽然发病机制可能是
多因素,如胸腺和淋巴纤维化,全身免疫激活和炎症,我们的
提出的病理性抗CD 4 IgG介导的CD 4 + T细胞耗竭提供了一种独特的靶向机制
CD 4 + T细胞。在本研究中,我们将探讨病理性抗-
免疫无应答者的CD 4 IgG和抗CD 4自身反应性B细胞,并确定治疗靶点
与传统ART一起预防抗CD 4 IgG介导的发病机制,以增加免疫恢复,
减少艾滋病毒阳性退伍军人和非退伍军人的并发症、发病率和死亡率。
AIM 1.确定抗CD 4 IgG对CD 4 + T细胞活化和功能以及HIV的病理活性
HIV+免疫无应答者中通过CD 4受体信号传导途径的潜伏期。
AIM 2.确定抗CD 4自身抗体的B细胞受体特征和基因表达谱-
从HIV+免疫无应答者产生B细胞。
AIM 3.确定病理性抗CD 4抗体的生化特性和共有抗原结合表位
HIV+免疫无应答者中的单克隆IgG。
这条线的调查具有很大的治疗潜力的退伍军人和非退伍军人艾滋病毒阳性
CD 4 + T细胞恢复差的个体,发病风险特别高的人群,
死亡率,因此是一个具有公共卫生重要性的领域。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Wei Jiang其他文献
General Solution and Observability of Singular Differential Systems with Delay
时滞奇异微分系统的一般解与可观测性
- DOI:
10.1155/2013/512465 - 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Wei Jiang - 通讯作者:
Wei Jiang
Wei Jiang的其他文献
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{{ truncateString('Wei Jiang', 18)}}的其他基金
Investigate Host Gene Isoforms Contributing to HIV Persistence in Cocaine Users
研究导致可卡因吸食者中艾滋病毒持续存在的宿主基因亚型
- 批准号:
10788990 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Investigate the mechanism of autoreactive B cell-mediated immunological failure despite virologic suppression in HIV-infected individuals on antiretroviral therapy
研究尽管接受抗逆转录病毒治疗的 HIV 感染者出现病毒学抑制,但自身反应性 B 细胞介导的免疫失败的机制
- 批准号:
10595555 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Investigate B cell perturbations and immune reconstitution failure in response to antiretroviral therapy in HIV-infected cocaine users
调查感染 HIV 的可卡因使用者抗逆转录病毒治疗导致的 B 细胞扰动和免疫重建失败
- 批准号:
10547870 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Investigate B cell perturbations and immune reconstitution failure in response to antiretroviral therapy in HIV-infected cocaine users
调查感染 HIV 的可卡因使用者抗逆转录病毒治疗导致的 B 细胞扰动和免疫重建失败
- 批准号:
10677040 - 财政年份:2022
- 资助金额:
-- - 项目类别:
On the pathogenic role of anti-CD4 antibody in poor CD4+ T cell recovery after antiretroviral therapy in HIV disease
抗 CD4 抗体在 HIV 疾病抗逆转录病毒治疗后 CD4 T 细胞恢复不良中的致病作用
- 批准号:
9921289 - 财政年份:2017
- 资助金额:
-- - 项目类别:
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:
8534019 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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:
8321994 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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:
8719000 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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