Transmission-blocking potential of novel HIV Env-specific mucosal antibodies

新型 HIV Env 特异性粘膜抗体的传播阻断潜力

• 批准号: 8603215
• 负责人: Sallie R. Permar
• 金额: $ 47.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-22 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603215
• 关键词: Antibodies; Antibody Formation; Antiviral Agents; B-Lymphocytes; Blood; Breast Feeding; Cell Separation; Cells; Characteristics; Chronic; Colostrum; Dendritic Cells; Development; Epitopes; Event; Genetic; Goals; Growth; Gut associated lymphoid tissue; HIV; HIV-1; Home environment; Human Milk; Immune response; Immunization; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Genes; In Vitro; Infant; Infection; Investigation; Macaca mulatta; Mammary gland; Maternal antibody; Mediating; Milk; Modeling; Monoclonal Antibodies; Mucous Membrane; Neonatal; Oral; Peripheral; Peripheral Blood Mononuclear Cell; Plasma; Population; Production; Recombinants; Role; Source; Specificity; Surface; Techniques; Technology; Vaccination; Vaccine Design; Vaccines; Viral; Viral Physiology; Virion; Virus; Woman; Work; antibody-dependent cell cytotoxicity; base; design; gastrointestinal; in vitro Assay; in vivo; mucosal site; neutralizing antibody; novel; pathogen; peripheral blood; postnatal; prevent; public health relevance; repository; response; simian human immunodeficiency virus; transmission process; vaccine development

DESCRIPTION: A successful HIV-1 vaccine must elicit immune responses that impede virus transmission at mucosal sites of virus exposure. However, HIV-1 vaccine development is hampered by a lack of understanding of the epitope-specificity and functional role of HIV-1 Envelope (Env)-specific antibodies produced by mucosal B cell populations. The goal of this proposal is to determine the ability of naturally-elicited mucosal antibodies to block mucosal HIV-1 transmission. Breast milk is a rich source of mucosal antibodies which represent the ontogeny of the gastrointestinal B cell population (the "gut-mammary axis"). Moreover, these mucosal antibodies may contribute to passive protection against HIV-1 acquisition in the majority of HIV-1-exposed, breastfed infants. We recently established the technology required for isolation of HIV-1 Env-specific B cells and recombinant production of their monoclonal antibodies (mAbs) from colostrum of HIV-infected, lactating women. Using this technique, we isolated novel HIV-1 Env-specific mucosal IgG and IgA antibodies from breast milk B cells, and demonstrated their neutralizing and nonneutralizing functions. As mucosal B cell responses are compartmentalized from those in peripheral blood, we hypothesize that the repertoire of HIV-1 Env-specific-IgG/IgA antibodies isolated from mammary B cells are genetically and functionally distinct to those isolated from peripheral B cells. In this proposal, we will 1) contrast the genetc characteristics and epitope-specificity of HIV-1 Env-specific antibodies produced by systemic and mucosal B cells isolated from a repository of breast milk and peripheral blood mononuclear cells of HIV-1-infected women; 2) identify qualities and epitope-specificities of mucosal HIV-1 Env-specific IgG and IgA antibodies that possess potent in vitro neutralizing and nonneutralizing functions that may block HIV-1 transmission; and 3) determine the ability of mucosally-produced HIV Env-specific IgG and IgA antibodies to protect against virus acquisition in vivo, using the neonatal rhesus monkey/oral simian-HIV (SHIV) transmission model. This work will set the standard for the type of mucosal antibody responses that an effective HIV-1 vaccine should target. Moreover, our work will define the mucosal HIV-1 Env-specific IgG and IgA antibody responses that can protect against HIV-1 transmission to infants via breastfeeding, establishing the maternal antibody responses required to eliminate postnatal HIV-1 transmission.

描述：成功的 HIV-1 疫苗必须引发免疫反应，阻止病毒在病毒暴露的粘膜部位传播。然而，由于对粘膜 B 细胞群产生的 HIV-1 包膜 (Env) 特异性抗体的表位特异性和功能作用缺乏了解，HIV-1 疫苗的开发受到阻碍。该提案的目标是确定自然产生的粘膜抗体阻止粘膜 HIV-1 传播的能力。母乳是粘膜抗体的丰富来源，代表胃肠道 B 细胞群（“肠-乳腺轴”）的个体发育。此外，这些粘膜抗体可能有助于被动保护大多数暴露于 HIV-1 的母乳喂养婴儿免受 HIV-1 感染。我们最近建立了从 HIV 感染的哺乳期妇女的初乳中分离 HIV-1 Env 特异性 B 细胞并重组生产其单克隆抗体 (mAb) 所需的技术。利用这种技术，我们从母乳 B 细胞中分离出新型 HIV-1 Env 特异性粘膜 IgG 和 IgA 抗体，并证明了它们的中和和非中和功能。由于粘膜 B 细胞反应与外周血中的反应区分开来，我们假设从乳腺 B 细胞分离的 HIV-1 Env 特异性 IgG/IgA 抗体库在遗传和功能上与从外周 B 细胞分离的抗体不同。在本提案中，我们将 1) 对比从 HIV-1 感染妇女的母乳和外周血单核细胞库中分离出的全身和粘膜 B 细胞产生的 HIV-1 Env 特异性抗体的基因特征和表位特异性； 2) 确定粘膜 HIV-1 Env 特异性 IgG 和 IgA 抗体的质量和表位特异性，这些抗体具有可能阻止 HIV-1 传播的有效体外中和和非中和功能； 3) 使用新生恒河猴/猿猴口腔 HIV (SHIV) 传播模型，确定粘膜产生的 HIV 包膜特异性 IgG 和 IgA 抗体防止体内病毒感染的能力。这项工作将为有效的 HIV-1 疫苗应针对的粘膜抗体反应类型设定标准。此外，我们的工作将定义粘膜 HIV-1 Env 特异性 IgG 和 IgA 抗体反应，可以防止 HIV-1 通过母乳喂养传播给婴儿，建立消除产后 HIV-1 传播所需的母体抗体反应。