Regulation of antibody diversification and production in HIV-1 infection
HIV-1 感染中抗体多样化和产生的调节
基本信息
- 批准号:8050194
- 负责人:
- 金额:$ 41.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAdaptor Signaling ProteinAffinityAntibodiesAntibody FormationAntigensAttenuatedB-LymphocytesBindingC-terminalCD4 Positive T LymphocytesCellsDNADataDefectDevelopmentDiseaseDisease ProgressionDoctor of MedicineEnzymesEventFunctional disorderFundingGenesGenetic RecombinationGoalsHIV-1Helper-Inducer T-LymphocyteHumoral ImmunitiesImmuneImmune systemImmunoglobulin AImmunoglobulin Class SwitchingImmunoglobulin DImmunoglobulin GImmunoglobulin MImmunoglobulin Somatic HypermutationImmunoglobulin Variable RegionIn VitroIndividualInfectionInterleukin-4InvadedIon ChannelJanus kinaseLeadLipidsLymphoidMediatingMembraneMembrane MicrodomainsMyeloid CellsN-terminalNanotubesOrganPaperPathogenesisPhosphotransferasesPhysiologicalPlasma CellsPoint MutationPrimatesPrincipal InvestigatorProductionProtein KinaseProteinsPublicationsPublishingRegulationSIVSignal PathwaySignal TransductionStructureStructure of germinal center of lymph nodeTNFRSF5 geneTNFSF5 geneTravelVaccinesVesicleViralViral AntigensViral ProteinsVirusWorkactivation-induced cytidine deaminaseantigen bindingdifferentiated B cellenv Gene Productsflexibilityin vivomacrophagemucosal sitemutantnovelnovel therapeuticsnovel vaccinespathogenprogramspublic health relevanceresponsetraffickingviral RNA
项目摘要
DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the mechanisms by which HIV-1 evades humoral immunity. Antibody responses, including class switch DNA recombination (CSR) and somatic hypermutation (SHM), are essential to block HIV-1 entry and spread. CSR substitutes IgM with IgG or IgA, thereby endowing antibodies with novel effector functions that enhance viral clearance systemically and at mucosal sites of entry. SHM introduces point mutations in genes encoding the antigen-binding variable region of antibodies, thereby providing the structural correlate for selection by viral antigens of higher affinity IgG and IgA mutants. CSR and SHM require activation-induced cytidine deaminase (AID), an enzyme expressed by B cells in the germinal center (GC) of secondary lymphoid organs. This specialized microenvironment comprises CD4+ T cells that activate B cells through CD154 and IL-4. Ultimately, GC B cells differentiate into plasma cells, which secrete large amounts of IgG and IgA antibodies. HIV-1 impairs systemic and mucosal IgG and IgA responses to viral antigens, opportunistic pathogens and vaccines through mechanisms that remain poorly understood. Although progressive loss of CD4+ T cells is certainly important, B cell-intrinsic abnormalities, including poor responsiveness of B cells to CD154, are also involved. In this proposal, we argue that the HIV-1 protein Nef contributes to the genesis of B cell-intrinsic defects arising during HIV-1 infection. We contend that Nef attenuates CD154-dependent CSR, SHM as well as virus-specific IgG and IgA production in systemic and mucosal GCs. We also hypothesize that Nef targets B cells by traveling through long-range tunneling nanotubules emanating from HIV-1-infected cells. Finally, we propose that multiple Nef domains contribute to the inhibition of kinases transducing CD154 and IL-4 signaling in B cells. Three specific aims are proposed. Aim 1 is to determine the ability of Nef-sufficient and Nef-deficient HIV-1 to attenuate CSR, SHM and antigen-specific IgG and IgA production in systemic and mucosal B cells. Aim 2 is to assess the ability of long- distance tunneling nanotubules to shuttle membrane-bound and vesicle-associated Nef from infected cells to B cells. Aim 3 is to elucidate the molecular interactions involved in Nef-mediated inhibition of CD154 and IL-4 signaling in B cells. Findings resulting from these studies should lead to a better understanding of the mechanisms whereby HIV-1 evades the antibody response. In addition, the proposed studies might facilitate the development of novel therapeutic and vaccine strategies against HIV-1.
PUBLIC HEALTH RELEVANCE: HIV-1 profoundly impairs antibody responses against viral proteins, opportunistic agents and vaccines. Growing evidence indicates that this antibody deficiency is caused not only by loss of CD4+ T cells, but also by B cell-intrinsic defects. The goal of this application is to elucidate the mechanisms by which HIV-1 causes B cell dysfunctions. Ultimately, findings deriving from the proposed studies should help develop more effective vaccines against HIV-1.
描述(由申请人提供):该提案的目的是阐明HIV-1逃避体液免疫的机制。抗体反应,包括类开关DNA重组(CSR)和体细胞超成名(SHM),对于阻止HIV-1进入和扩散至关重要。 CSR用IgG或IgA替代IgM,从而赋予具有新型效应函数的抗体,从而在系统地和粘膜入口部位增强病毒清除率。 SHM引入了编码抗体结合变量区域的基因中的点突变,从而提供了通过较高亲和力IgG和IgA突变体的病毒抗原选择的结构相关性。 CSR和SHM需要激活诱导的胞苷脱氨酶(AID),这是一种由B细胞在继发性淋巴机构的生发中心(GC)中表达的酶。这种专门的微环境包括通过CD154和IL-4激活B细胞的CD4+ T细胞。最终,GC B细胞分化为浆细胞,分泌大量的IgG和IgA抗体。 HIV-1通过保持较熟悉的机制,损害了系统性和粘膜IgG,以及对病毒抗原,机会性病原体和疫苗的反应。尽管CD4+ T细胞的进行性丧失肯定很重要,但B细胞中性异常(包括B细胞对CD154的反应性较差)也涉及。在此提案中,我们认为HIV-1蛋白NEF有助于HIV-1感染期间引起的B细胞中性缺陷的起源。我们认为,NEF会减弱全身和粘膜GC中依赖CD154依赖性的CSR,SHM以及病毒特异性IgG和IgA的产生。我们还假设NEF通过从HIV-1感染的细胞发出的远程隧道纳米管中传播NEF靶向B细胞。最后,我们提出多个NEF结构域有助于抑制B细胞中CD154和IL-4信号转导的激酶。提出了三个具体目标。目的1是确定NEF缺乏和NEF缺乏的HIV-1在全身和粘膜B细胞中减弱CSR,SHM和抗原特异性IgG和IgA产生的能力。 AIM 2是评估长距离隧穿纳米管从感染细胞到B细胞的膜结合和囊泡相关的NEF的能力。目的3是阐明与NEF介导的B细胞中CD154和IL-4信号传导有关的分子相互作用。这些研究产生的发现应导致对HIV-1逃避抗体反应的机制有更好的了解。此外,拟议的研究可能有助于开发针对HIV-1的新型治疗和疫苗策略。
公共卫生相关性:HIV-1严重损害了针对病毒蛋白,机会主义剂和疫苗的抗体反应。越来越多的证据表明,这种抗体缺乏症不仅是由于CD4+ T细胞的丧失而引起的,而且还由B细胞中性缺陷引起。该应用的目的是阐明HIV-1引起B细胞功能障碍的机制。最终,从提出的研究中得出的发现应有助于开发针对HIV-1的更有效的疫苗。
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(1)
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ANDREA CERUTTI其他文献
ANDREA CERUTTI的其他文献
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{{ truncateString('ANDREA CERUTTI', 18)}}的其他基金
Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
解码 HIV-1 感染肠道中微生物群与 B 细胞相互作用:对免疫无反应者的影响
- 批准号:
10626870 - 财政年份:2020
- 资助金额:
$ 41.53万 - 项目类别:
Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
解码 HIV-1 感染肠道中微生物群与 B 细胞相互作用:对免疫无反应者的影响
- 批准号:
10414937 - 财政年份:2020
- 资助金额:
$ 41.53万 - 项目类别:
Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
解码 HIV-1 感染肠道中微生物群与 B 细胞相互作用:对免疫无反应者的影响
- 批准号:
9894545 - 财政年份:2020
- 资助金额:
$ 41.53万 - 项目类别:
Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
解码 HIV-1 感染肠道中微生物群与 B 细胞相互作用:对免疫无反应者的影响
- 批准号:
10160898 - 财政年份:2020
- 资助金额:
$ 41.53万 - 项目类别:
Dissecting The Interplay of GM-CSF and Neutrophils In IgG and IgA Responses
剖析 GM-CSF 和中性粒细胞在 IgG 和 IgA 反应中的相互作用
- 批准号:
8516868 - 财政年份:2013
- 资助金额:
$ 41.53万 - 项目类别:
Regulation and Function of Immunoglobulin D in Mucosal Immune Defense
免疫球蛋白 D 在粘膜免疫防御中的调节和功能
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8508845 - 财政年份:2011
- 资助金额:
$ 41.53万 - 项目类别:
Dissecting The Interplay of GM-CSF and Neutrophils In IgG and IgA Responses
剖析 GM-CSF 和中性粒细胞在 IgG 和 IgA 反应中的相互作用
- 批准号:
8198166 - 财政年份:2011
- 资助金额:
$ 41.53万 - 项目类别:
Regulation and Function of Immunoglobulin D in Mucosal Immune Defense
免疫球蛋白 D 在粘膜免疫防御中的调节和功能
- 批准号:
8296171 - 财政年份:2011
- 资助金额:
$ 41.53万 - 项目类别:
Regulation and Function of Immunoglobulin D in Mucosal Immune Defense
免疫球蛋白 D 在粘膜免疫防御中的调节和功能
- 批准号:
8180217 - 财政年份:2011
- 资助金额:
$ 41.53万 - 项目类别:
Regulation of antibody diversification and production in HIV-1 infection
HIV-1 感染中抗体多样化和产生的调节
- 批准号:
7586170 - 财政年份:2008
- 资助金额:
$ 41.53万 - 项目类别:
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