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

描述：成功的HIV-1疫苗必须在病毒暴露的粘膜部位引发免疫应答，阻止病毒传播。然而，HIV-1疫苗的开发受到了阻碍，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理解。这项提议的目的是确定自然引起的粘膜抗体阻断粘膜HIV-1传播的能力。母乳是代表胃肠道B细胞群（“肠道-乳房轴”）个体发育的粘膜抗体的丰富来源。此外，这些粘膜抗体可能有助于被动保护大多数HIV-1暴露的母乳喂养婴儿免受HIV-1感染。我们最近建立了分离HIV-1 Env特异性B细胞并从HIV感染的哺乳期妇女的初乳中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细胞中分离了新的HIV-1 Env特异性粘膜IgG和伊加抗体，并证明了它们的中和和非中和功能。由于粘膜B细胞应答与外周血中的应答区室化，我们假设从乳腺B细胞分离的HIV-1 Env特异性IgG/伊加抗体库在遗传和功能上与从外周B细胞分离的那些不同。在这个建议中，我们将1）对比由从HIV-1感染妇女的母乳和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 Env特异性抗体的基因特征和表位特异性; 2）鉴定粘膜HIV-1 Env的质量和表位特异性，特异性IgG和伊加抗体，具有有效的体外中和和非中和功能，可阻断HIV-1传播;和3）使用新生恒河猴/经口猿猴-HIV（SHIV）传播模型，测定粘膜产生的HIV Env特异性IgG和伊加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疫苗应该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和伊加抗体应答，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应答。

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.