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
• 负责人: ANDREA CERUTTI
• 金额: $ 42万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/7586170
• 关键词: Abbreviations; Adaptor Signaling Protein; Affinity; Antibodies; Antibody Formation; Antigens; Attenuated; B-Lymphocytes; Binding; C-terminal; CD4 Positive T Lymphocytes; Cells; Data; Defect; Development; Disease; Disease Progression; Doctor of Medicine; Enzymes; Event; Functional disorder; Funding; Gagging; 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; 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; gag Gene Products; in vivo; macrophage; mucosal site; mutant; nef Protein; novel; novel therapeutics; pathogen; programs; public health relevance; response; therapeutic vaccine; trafficking; viral RNA

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(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，包括类开关DNA重组(CSR)和体细胞超突变(SHM)，是阻止HIV-1入侵和传播的关键。CSR用Ig G或Ig A取代Ig M，从而赋予抗体新的效应功能，增强病毒在系统和进入粘膜部位的清除。SHM在编码抗体的抗原结合可变区的基因中引入了点突变，从而为高亲和力的病毒抗原选择免疫球蛋白和免疫球蛋白A突变体提供了结构相关性。CSR和SHM需要激活诱导型胞苷脱氨酶(AID)，这是一种由次级淋巴器官生发中心(GC)的B细胞表达的酶。这种特殊的微环境由CD4+T细胞组成，通过CD154和IL-4激活B细胞。最终，GC B细胞分化为浆细胞，浆细胞分泌大量的Ig G和Ig A抗体。HIV-1通过尚不清楚的机制损害系统和粘膜对病毒抗原、机会性病原体和疫苗的免疫球蛋白和免疫球蛋白A反应。虽然CD4+T细胞的进行性丧失当然是重要的，但B细胞固有的异常，包括B细胞对CD154的低反应性，也与此有关。在这项建议中，我们认为HIV-1蛋白Nef在HIV-1感染过程中产生的B细胞固有缺陷的发生中起作用。我们认为Nef可以减少依赖CD154的CSR、SHM以及系统和粘膜GC中病毒特异性的免疫球蛋白和免疫球蛋白A的产生。我们还假设Nef通过长距离隧道传输来自HIV-1感染细胞的纳米管来靶向B细胞。最后，我们认为多个Nef结构域在抑制B细胞中的CD154和IL-4信号转导通路中起作用。提出了三个具体目标。目的1确定Nef充足和Nef缺陷的HIV-1对系统和粘膜B细胞产生CSR、SHM和抗原特异性的Ig G和Ig A的能力。目的2是评估长距离隧道纳米管将膜结合和囊泡相关的Nef从感染细胞运送到B细胞的能力。目的3阐明Nef介导抑制B细胞CD154和IL-4信号转导的分子相互作用。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，拟议的研究可能有助于开发针对HIV-1的新的治疗和疫苗策略。 公共卫生相关性：HIV-1严重损害了对病毒蛋白、机会性因素和疫苗的抗体反应。越来越多的证据表明，这种抗体缺陷不仅是由于CD4+T细胞的丧失，也是由于B细胞的固有缺陷。这项应用的目的是阐明HIV-1导致B细胞功能障碍的机制。最终，拟议研究得出的结果应该有助于开发更有效的艾滋病毒-1疫苗。