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：
ANDREA CERUTTI
金额：
$ 41.53万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
https://reporter.nih.gov/project-details/8050194
关键词：
Abbreviations Adaptor Signaling Protein Affinity Antibodies Antibody Formation Antigens Attenuated B-Lymphocytes Binding C-terminal CD4 Positive T Lymphocytes Cells DNA Data Defect Development Disease Disease Progression Doctor of Medicine Enzymes Event Functional disorder Funding Genes Genetic Recombination Goals HIV-1 Helper-Inducer T-Lymphocyte Humoral Immunities Immune Immune system Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin D Immunoglobulin G Immunoglobulin M Immunoglobulin Somatic Hypermutation Immunoglobulin Variable Region In Vitro Individual Infection Interleukin-4 Invaded Ion Channel Janus kinase Lead Lipids Lymphoid Mediating Membrane Membrane Microdomains Myeloid Cells N-terminal Nanotubes Organ Paper Pathogenesis Phosphotransferases Physiological Plasma Cells Point Mutation Primates Principal Investigator Production Protein Kinase Proteins Publications Publishing Regulation SIV Signal Pathway Signal Transduction Structure Structure of germinal center of lymph node TNFRSF5 gene TNFSF5 gene Travel Vaccines Vesicle Viral Viral Antigens Viral Proteins Virus Work activation-induced cytidine deaminase antigen binding differentiated B cell env Gene Products flexibility in vivo macrophage mucosal site mutant novel novel therapeutics novel vaccines pathogen programs public health relevance response trafficking viral 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）：本提案的目的是阐明 HIV-1 逃避体液免疫的机制。抗体反应，包括类别转换 DNA 重组 (CSR) 和体细胞超突变 (SHM)，对于阻止 HIV-1 进入和传播至关重要。 CSR 用 IgG 或 IgA 替代 IgM，从而赋予抗体新的效应功能，增强全身和粘膜进入部位的病毒清除。 SHM 在编码抗体抗原结合可变区的基因中引入点突变，从而为更高亲和力 IgG 和 IgA 突变体的病毒抗原的选择提供结构相关性。 CSR 和 SHM 需要激活诱导的胞苷脱氨酶 (AID)，这是一种由次级淋巴器官生发中心 (GC) 中的 B 细胞表达的酶。这种特殊的微环境由 CD4+ T 细胞组成，可通过 CD154 和 IL-4 激活 B 细胞。最终，GC B细胞分化为浆细胞，分泌大量IgG和IgA抗体。 HIV-1 通过仍知之甚少的机制损害全身和粘膜 IgG 和 IgA 对病毒抗原、机会性病原体和疫苗的反应。尽管 CD4+ T 细胞的逐渐丧失固然很重要，但 B 细胞固有的异常（包括 B 细胞对 CD154 的反应性差）也参与其中。在该提案中，我们认为 HIV-1 蛋白 Nef 有助于 HIV-1 感染期间出现的 B 细胞内在缺陷的发生。我们认为 Nef 减弱了全身和粘膜 GC 中 CD154 依赖性 CSR、SHM 以及病毒特异性 IgG 和 IgA 的产生。我们还假设 Nef 通过穿过 HIV-1 感染细胞发出的长程隧道纳米管来靶向 B 细胞。最后，我们提出多个 Nef 结构域有助于抑制 B 细胞中转导 CD154 和 IL-4 信号传导的激酶。提出了三个具体目标。目标 1 是确定 Nef 充足和 Nef 缺陷的 HIV-1 减弱全身和粘膜 B 细胞中 CSR、SHM 以及抗原特异性 IgG 和 IgA 产生的能力。目标 2 是评估长距离隧道纳米管将膜结合和囊泡相关的 Nef 从受感染细胞转运到 B 细胞的能力。目标 3 是阐明 Nef 介导的 B 细胞中 CD154 和 IL-4 信号传导抑制所涉及的分子相互作用。这些研究的结果应该有助于更好地理解 HIV-1 逃避抗体反应的机制。此外，拟议的研究可能会促进针对 HIV-1 的新型治疗和疫苗策略的开发。公共卫生相关性：HIV-1 严重损害针对病毒蛋白、机会性药物和疫苗的抗体反应。越来越多的证据表明，这种抗体缺陷不仅是由 CD4+ T 细胞的损失引起的，而且也是由 B 细胞固有的缺陷引起的。本申请的目的是阐明 HIV-1 导致 B 细胞功能障碍的机制。最终，拟议研究的结果应有助于开发更有效的 HIV-1 疫苗。