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: 9267899
• 负责人: Sallie R. Permar
• 金额: $ 60.21万
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267899
• 关键词: Antibodies; Antibody Response; Antiviral Agents; B-Lymphocytes; Blood; Breast Feeding; Breastfed infant; 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; Lactation; 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; vaccine trial; 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：一种成功的HIV-1疫苗必须引起免疫反应，以阻止病毒在接触病毒的粘膜部位传播。然而，由于缺乏对粘膜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的了解，HIV-1疫苗的开发受到了阻碍。这项提议的目标是确定自然诱导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，它代表了胃肠道B细胞群体(“肠道-乳腺轴”)的个体发育。此外，这些粘膜抗体可能有助于在大多数接触艾滋病毒-1的母乳喂养婴儿中被动预防艾滋病毒-1感染。我们最近建立了从感染艾滋病毒的哺乳期妇女的初乳中分离HIV-1环境特异性B细胞并重组生产其单抗(MAbb)所需的技术。利用这项技术，我们从母乳B细胞中分离出了新的HIV-1Env特异性粘膜抗体，并证明了它们的中和和非中和功能。由于粘膜B细胞的反应与外周血中的反应是分开的，我们假设从乳腺B细胞中分离的HIV-1Env特异性Ig G/Ig A抗体在遗传和功能上与从外周B细胞中分离的抗体有所不同。在这项建议中，我们将1)比较从母乳和HIV-1感染妇女的外周血单核细胞库中分离的系统和粘膜B细胞产生的HIV-1环境特异性抗体的基因特征和表位特异性；2)鉴定粘膜中HIV-1环境特异性的抗体的性质和表位特异性，这些抗体在体外具有有效的中和和非中和功能，可以阻断HIV-1的传播；以及3)使用新生恒河猴/口腔猴HIV(SHIV)传播模型，确定粘膜产生的HIV Env特异性的Ig G和Ig A抗体在体内防止病毒获得的能力。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，我们的工作将确定粘膜中HIV-1环境特异性的抗体反应，可以防止艾滋病毒-1通过母乳喂养传播给婴儿，建立消除出生后艾滋病毒-1传播所需的母体抗体反应。

项目成果

Predominant envelope variable loop 2-specific and gp120-specific antibody-dependent cellular cytotoxicity antibody responses in acutely SIV-infected African green monkeys.

• DOI: 10.1186/s12977-018-0406-5
• 发表时间: 2018-03-09
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Nguyen QN;Martinez DR;Himes JE;Whitney Edwards R;Han Q;Kumar A;Mangan R;Nicely NI;Xie G;Vandergrift N;Shen X;Pollara J;Permar SR
• 通讯作者: Permar SR