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（由适用提供）：抗体（ABS）在预防HIV-1感染中的作用首先是通过多种动物模型中的多种被动免疫抑制实验确定的。但是，开发有效的HIV疫苗诱导的保护性ABS是现代医学的主要挑战。除RV144疫苗试验外，过去的努力导致了令人失望的结果。在RV144疫苗的接受者中，高水平的血浆抗V2 ABS与HIV-1感染的风险降低相关。但是，V2抗体是否直接预防感染，还是V2 ABS与疫苗效率相关。为了解决这些问题，必须进行非人类隐私的实验，因为该模型对人类具有最相似的免疫反应。这就是我们建议研究抗V2单克隆ABS（mAb）的各种抑制作用，以及恒河猕猴中疫苗诱导的粘膜抗V2 ABS的机械作用，即这些抗体是否仅保护单独使用SHIV挑战，还是与其他抗Hiv-Hiv-1 Envelope（Envelope（Envelope）（Envelope（Envelope））抗体。我们假设抗V2 ABS抑制了GP120/α4β7整合素相互作用以及HIV-1与表达α4β7，CD4和CCR5的Th17细胞的结合。由于TH17细胞主要位于粘膜组织中，我们预测抗V2 ABS的诱导会在粘膜分泌中局部增加V2 ABS的滴度，并更有效地阻止病毒与靶T细胞的结合，从而防止HIV-1感染。为了检验这一假设，我们将与GP120 ABS相比，用V1V2融合蛋白免疫猕猴，以诱导粘膜和全身性抗V2 ABS，并挑战具有SHIV的动物，以确定V2 ABS的保护潜力。抗V2 ABS的可能抑制作用，包括神经化，FC介导的活性和抑制GP120/α4β7相互作用，将使用我们实验室中在同时IgG1和IgG3的实验室中产生的人V2 MAB进行测试（AIM 1）。这些研究将确定由疫苗诱导的粘膜和/或全身性抗V2 ABS介导的抑制活性的类型和范围。猕猴将使用GP120 DNA Prime和蛋白质增强进行免疫，包括在粘膜组织处施用的V1V2融合蛋白，并与全身性GP120进行比较，并与具有CM244病毒的匹配序列进行了比较。 AIM 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 ABS的发展（AIM 2）。为了确定疫苗效率，在粘膜阴道和直肠分泌中检测到的抗V2 ABS的免疫猕猴将受到多种低剂量的阴道Shiv-Bal接种的挑战（AIM 3）。拟议的研究旨在测试抗V2抗体是否具有保护SHIV挑战或减少病毒负荷的能力，以及粘膜V2抗体是否比全身V2抗体具有任何优势。这项研究的结果将带来实际的后果，以告知HIV疫苗的设计，以诱导全身性抗V2 ABS的高滴度以及其他ABS，或包括鼻内免疫以诱导粘膜抗V2 ABS以提高疫苗的效率。