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: 9059553
• 负责人: Sallie R. Permar
• 金额: $ 76.71万
• 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/9059553
• 关键词: Antibodies; Antibody Response; 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; HIV-1 vaccine; 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; viral transmission

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疫苗必须引起免疫反应，这会阻碍病毒暴露的粘膜部位传播。然而，由于缺乏对粘膜B细胞群体产生的HIV-1 Invelope（ENK）特异性抗体的表位特异性和功能作用的了解，HIV-1疫苗的发育受到阻碍。该提案的目的是确定自然吸收的粘膜抗体阻断粘膜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细胞种群的个体发育（“肠乳腺轴”）。此外，这些粘膜抗体可能有助于在大多数暴露于HIV-1的母乳喂养婴儿中对HIV-1获取的被动保护。我们最近建立了分离HIV-1 ENV特异性B细胞的技术，并从HIV感染的哺乳期妇女的初乳中重组产生其单克隆抗体（MAB）。使用这种技术，我们从母乳B细胞中分离了新型的HIV-1 Env特异性粘膜IgG和IgA抗体，并证明了它们中和和非中和化功能。由于粘膜B细胞反应是从外周血中的粘膜B细胞反应分隔的，因此我们假设从乳腺B细胞中分离出的HIV-1 ENV特异性-IGG/IGA抗体的曲目在遗传上和功能上与与外周B细胞分离的曲线在功能上与众不同。在此提案中，我们将1）对比由从母乳和外周血血液单核细胞中分离出的HIV-1和粘膜B细胞产生的HIV-1 ENV特异性抗体的遗传学特征和表位特异性； 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，这些抗体具有有效的体外中和和非中和化功能，这些功能可能阻止HIV-1传播； 3）确定使用新生儿恒河猴/口腔猴子-HIV（SHIV）透射模型，确定粘液生产的HIV ENV特异性IgG和IgA抗体预防体内病毒的能力。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，这些反应可以通过母乳喂养来防止HIV-1向婴儿传播，从而确定消除产后HIV-1传播所需的母体抗体反应。