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

描述：成功的HIV-1疫苗必须引起免疫反应，在病毒暴露的粘膜部位阻止病毒传播。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疫苗的开发受到阻碍。这项提议的目的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（“肠-乳腺轴”）的个体发生。此外，在大多数HIV-1暴露的母乳喂养婴儿中，这些粘膜抗体可能有助于对HIV-1获得的被动保护。我们最近建立了从感染hiv的哺乳期妇女初乳中分离HIV-1 env特异性B细胞和重组其单克隆抗体（mab）所需的技术。利用这种技术，我们从母乳B细胞中分离出新的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细胞的反应与外周血中的反应是区隔的，我们假设从乳腺B细胞中分离出的HIV-1 env特异性igg /IgA抗体在遗传和功能上与从外周血B细胞中分离出的抗体不同。在本研究中，我们将1)比较HIV-1 env特异性抗体的基因特征和表位特异性，这些抗体是由从HIV-1感染妇女的母乳和外周血单个核细胞中分离出来的全身和粘膜B细胞产生的；2)鉴定粘膜HIV-1 env特异性IgG和IgA抗体的性质和表位特异性，这些抗体具有有效的体外中和和非中和功能，可能阻断HIV-1的传播；3)利用新生恒河猴/口腔猿猴-HIV （SHIV）传播模型，确定粘膜产生的HIV env特异性IgG和IgA抗体在体内保护病毒获得的能力。这项工作将为有效的HIV-1疫苗应该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HIV-1 env特异性IgG和IgA抗体反应，这些抗体反应可以防止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。

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.