Protective role of V2 antibodies induced at mucosal tissues in macaques

猕猴粘膜组织中诱导的 V2 抗体的保护作用

• 批准号: 9187975
• 负责人: MIROSLAW K GORNY
• 金额: $ 73.63万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187975
• 关键词: Address; Adhesions; Amino Acid Motifs; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Binding; Binding Sites; Biological Assay; Blood; CCR5 gene; Cells; Chimeric Proteins; Clinical Trials; Control Animal; DNA; Dose; Epithelial Cells; Genital system; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Human; IgG1; IgG3; Immune; Immune response; Immunization; Immunize; Immunoglobulin Fragments; Infection; Infection prevention; Integrins; Intramuscular; Laboratories; Macaca; Macaca mulatta; Mediating; Modeling; Modern Medicine; Molecular; Monitor; Monoclonal Antibodies; Mucous Membrane; Passive Immunization; Plasma; Play; Proteins; Regimen; Research; Risk; Role; Route; SIV; Sampling; Serum; Specimen; Surface; T-Lymphocyte; Techniques; Testing; Tissues; Transudate; Vaccination; Vaccine Clinical Trial; Vaccines; Vagina; Viral Load result; Virus; Virus Diseases; base; cervicovaginal; design; experimental study; inhibiting antibody; integrin alpha4beta7; nonhuman primate; protective effect; public health relevance; receptor; rectal; simian human immunodeficiency virus; transcytosis; transmission process; vaccine development; vaccine efficacy; vaccine evaluation; vaccine trial; vector

 DESCRIPTION (provided by applicant): The role of antibodies (Abs) in preventing infection with HIV-1 has been firmly established by a multitude of passive immunization experiments in several animal models. However, developing an effective HIV vaccine inducing protective Abs is a major challenge for modern medicine. Past efforts yielded disappointing results with the exception of the RV144 vaccine trial. In recipients of the RV144 vaccine, high levels of plasma anti-V2 Abs correlate inversely with reduced risk of HIV-1 infection. However, whether the V2 antibodies directly protect against infection or whether the V2 Abs correlate with vaccine efficacy remains unknown. To address these questions, experiments in non-human primates are necessary, since this model has the most similar immune response to humans. Thus, we propose to study the various inhibitory functions of anti-V2 monoclonal Abs (mAbs) and the mechanistic effect of vaccine-induced mucosal anti-V2 Abs in rhesus macaques, i.e., whether these antibodies protect against SHIV challenge alone or in cooperation with other anti-HIV-1 envelope (Env) antibodies. We hypothesize that anti-V2 Abs inhibit the gp120/α4β7 integrin interaction and block binding of HIV-1 to Th17 cells expressing α4β7, CD4 and CCR5. As Th17 cells are mainly located in the mucosal tissues, we predict that induction of anti-V2 Abs locally increases the titer of V2 Abs in mucosal secretions and more efficiently blocks virus binding to target T cells, resulting in protection against HIV-1 infection. To test this hypothesis, we will immunize rhesus macaques with V1V2 fusion protein to induce mucosal and systemic anti-V2 Abs compared to gp120 Abs and challenge the animals with SHIV to determine the protective potentials of V2 Abs. The possible inhibitory functions of anti-V2 Abs, including neutralization, Fc-mediated activities and inhibition the gp120/α4β7 interaction, will be tested using human V2 mAbs produced in our lab in both isotypes IgG1 and IgG3 (Aim 1). These studies will determine the type and range of inhibitory activities mediated by vaccine-induced mucosal and/or systemic anti-V2 Abs. The macaques will be immunized using gp120 DNA prime and protein boost including V1V2-fusion protein administered at mucosal tissues, systemically and compared to systemic gp120 with matching sequence of CM244 virus. The most representative inhibitory functions defined in Aim 1 will be used to monitor the development of vaccine-induced V2 Abs in serum and mucosal secretions (Aim 2). To determine vaccine efficiency, the immunized macaques with detected anti-V2 Abs in mucosal vaginal and rectal secretions will be challenged by multiple low doses of vaginal SHIV-BaL inoculation (Aim 3). The proposed study is designed to test whether anti-V2 antibodies have ability to protect from SHIV challenge or reduce the viral load and whether mucosal V2 antibodies have any advantage over systemic V2 antibodies. The results of this research will have practical consequences to inform the design of HIV vaccine to induce either a high titer of systemic anti-V2 Abs along with other Abs or include intranasal immunization to induce mucosal anti-V2 Abs to increase vaccine efficacy.

 描述（由申请人提供）：抗体 (Abs) 在预防 HIV-1 感染中的作用已通过在多种动物模型中进行的大量被动免疫实验得到牢固确立。然而，开发一种有效的诱导保护性抗体的艾滋病毒疫苗是现代医学面临的重大挑战。除了 RV144 疫苗试验之外，过去的努力取得了令人失望的结果。在 RV144 疫苗接种者中，高水平的血浆抗 V2 抗体与 HIV-1 感染风险降低呈负相关。然而，V2 抗体是否直接预防感染或 V2 抗体是否与疫苗功效相关仍不清楚。为了解决这些问题，有必要在非人类灵长类动物身上进行实验，因为该模型具有与人类最相似的免疫反应。因此，我们建议在恒河猴中研究抗V2单克隆抗体（mAb）的各种抑制功能以及疫苗诱导的粘膜抗V2抗体的机制效应，即这些抗体是否单独或与其他抗HIV-1包膜（Env）抗体合作防止SHIV攻击。我们假设抗 V2 抗体抑制 gp120/α4β7 整合素相互作用，并阻止 HIV-1 与表达 α4β7、CD4 和 CCR5 的 Th17 细胞结合。由于 Th17 细胞主要位于粘膜组织，我们预测局部抗 V2 抗体的诱导会增加粘膜分泌物中 V2 抗体的滴度，并更有效地阻止病毒与靶 T 细胞结合，从而防止 HIV-1 感染。为了检验这一假设，我们将使用 V1V2 融合蛋白对恒河猴进行免疫，以诱导粘膜和全身抗 V2 抗体（与 gp120 抗体相比），并用 SHIV 攻击动物以确定 V2 抗体的保护潜力。抗 V2 抗体的可能抑制功能，包括中和、Fc 介导的活性和抑制 gp120/α4β7 相互作用，将使用我们实验室生产的同种型 IgG1 和 IgG3 的人 V2 mAb 进行测试（目标 1）。这些研究将确定疫苗诱导的粘膜和/或全身抗 V2 抗体介导的抑制活性的类型和范围。猕猴将使用 gp120 DNA 初免和蛋白质增强（包括在粘膜组织施用 V1V2 融合蛋白）进行全身免疫，并与具有匹配的 CM244 病毒序列的全身 gp120 进行比较。目标 1 中定义的最具代表性的抑制功能将用于监测血清和粘膜分泌物中疫苗诱导的 V2 Ab 的发展（目标 2）。为了确定疫苗效率，在阴道粘膜和直肠分泌物中检测到抗 V2 抗体的免疫猕猴将接受多次低剂量的阴道 SHIV-BaL 接种（目标 3）。拟议的研究旨在测试抗 V2 抗体是否具有保护免受 SHIV 攻击或减少病毒载量的能力，以及粘膜 V2 抗体是否比全身 V2 抗体有任何优势。这项研究的结果将产生实际影响，为 HIV 疫苗的设计提供信息，以诱导高滴度的全身性抗 V2 抗体以及其他抗体，或包括鼻内免疫以诱导粘膜抗 V2 抗体以提高疫苗功效。