Accumulation of VH replacement products in HIV patients

HIV患者中VH替代产品的积累

• 批准号: 8501719
• 负责人: Zhixin Zhang
• 金额: $ 45.31万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501719
• 关键词: Affect; Amino Acids; Antibodies; Antibody Formation; Antibody Repertoire; Antigens; Autoantibodies; B-Cell Development; B-Lymphocytes; Back; Bacterial Infections; Binding; CD19 gene; Cells; Charge; Chronic; Clonal Anergy; Clonal Deletion; Computers; Databases; Exons; Future; Gene Family; Generations; Genes; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; Human; Immune response; Immune system; Immunoglobulin Genes; Immunoglobulin Variable Region; Individual; Infection; Mature B-Lymphocyte; Mediating; Memory B-Lymphocyte; Mutation; Patients; Peptides; Plasmablast; Process; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Recombinant Antibody; Reverse Transcriptase Polymerase Chain Reaction; Superantigens; Testing; V(D)J Recombination; Vaccination; Vaccine Design; Vaccines; Viral Antibodies; Viral Antigens; Viral Genome; Viral Load result; Virus; Virus Diseases; base; neutralizing antibody; novel; prevent; protein structure; receptor; response; transmission process

DESCRIPTION (provided by applicant): Neutralizing antibodies are important effectors in humoral immune responses against bacterial or viral infections, including HIV. However, it is difficult to elicit effective neutralizing antibody responses against HIV in natural infections or y conventional vaccine approaches. Previous studies of HIV viral genome and envelop protein structures have suggested that HIV has evolved many strategies to avoid neutralizing antibody responses. Recent studies of neutralizing antibodies and anti-gp120 antibodies derived from HIV elite controllers showed that most of these antibodies are polyreactive, which are not generally tolerated during B cell development. VH replacement is normally considered as a receptor editing mechanism to change non- functional IgH genes or IgH genes encoding autoreactive antibodies. We found that VH replacement products are highly enriched in IgH genes derived from plasmablasts of HIV patients and the majority of these accumulated VH replacement products encode anti-gp120 and polyreactive antibodies. Moreover, treatment of EU12 mHC+ cells with gp120 proteins induces Ca++ influx in a BCR dependent manner and also induces VH replacement. Based on these results, we hypothesize that persistent HIV gp120 antigens induce VH replacement in the immature B cells in HIV infected patients; the resulting mature B cells expressing VH replacement products are positively selected later during anti-HIV response to generate anti-HIV and self/polyreactive antibodies. To test this hypothesis, (1) we will determine if VH replacement products are enriched in HIV patients; (2) we will determine if the accumulated VH replacement products encode anti-HIV and self/polyreactive antibodies; (3) we will determine if VH replacement is induced in the immature B cells of HIV patients and determine if gp120 induces VH replacement in human immature B cells. We will further determine if modulation of BCR signaling enhances gp120 induced VH replacement. Induction of VH replacement in the immature B cells and positive selection of mature B cells expressing VH replacement products during anti-HIV response are two different processes triggered by HIV viral antigens during chronic HIV infection. Understanding the underlying mechanisms will allow us to regulate VH replacement and facilitate the generation of effective anti-HIV antibodies in future vaccine design.

描述（由申请方提供）：中和抗体是针对细菌或病毒感染（包括HIV）的体液免疫应答中的重要效应物。然而，在自然感染或常规疫苗方法中很难引起针对HIV的有效中和抗体应答。先前对HIV病毒基因组和包膜蛋白结构的研究表明，HIV已经进化出许多策略来避免中和抗体反应。最近对来自HIV精英控制者的中和抗体和抗gp 120抗体的研究表明，这些抗体中的大多数是多反应性的，在B细胞发育期间通常不耐受。VH置换通常被认为是改变非功能性IgH基因或编码自身反应性抗体的IgH基因的受体编辑机制。我们发现，VH替代产品是高度富集的IgH基因来源于浆母细胞的HIV患者和大多数这些积累的VH替代产品编码抗gp 120和多反应性抗体。此外，用gp 120蛋白处理EU 12 MHC+细胞以BCR依赖性方式诱导Ca++内流，并且还诱导VH置换。基于这些结果，我们假设持续的HIV gp 120抗原诱导HIV感染患者的未成熟B细胞中的VH置换;所产生的表达VH置换产物的成熟B细胞在抗HIV应答期间被阳性选择，以产生抗HIV和自身/多反应性抗体。为了检验这一假设，（1）我们将确定VH置换产物是否在HIV患者中富集;（2）我们将确定累积的VH置换产物是否编码抗HIV和自身/多反应性抗体;（3）我们将确定VH置换是否在HIV患者的未成熟B细胞中诱导，并确定gp 120是否在人未成熟B细胞中诱导VH置换。我们将进一步确定BCR信号的调节是否增强gp 120诱导的VH置换。在慢性HIV感染过程中，HIV病毒抗原触发了两个不同的过程，即诱导未成熟B细胞中的VH置换和在抗HIV应答过程中表达VH置换产物的成熟B细胞的阳性选择。了解潜在的机制将使我们能够调节VH替代，并促进在未来的疫苗设计中产生有效的抗HIV抗体。