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

基本信息

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
项目类别：
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

项目摘要

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（通过应用程序证明）：抗体（ABS）在HIV-1生产中的作用已被众多的SIVE免疫实验在严重性动物模型中实验。药物。高水平的血浆抗V2 ABS与HIV-1感染的风险降低了。模型对人类具有最相似的免疫反应。或与其他抗体合作。我们预测，抗V2 ABS的产业会在粘膜分泌物中增加V2 ABS的滴度，并且更有效地阻止了与HIV-1感染保护的靶标的病毒结合。蛋白质诱导粘膜和全身性抗V2 ABS并用动物来挑战动物以确定V2的保护潜力。抗V2 ABS可能的抑制作用，包括中和，FC介导的激活性阳性，GP120/α44β7的相互作用将被测试在我们的实验室同种型IgG1和IgG3中产生的V2 mAB（AM 1）。与全身性GP120与CM244病毒相匹配的粘膜组织和粘液组织的抑制作用。粘膜阴道中的V2 ABS和重新分泌物将是挑战性低剂量的阴道Shiv-Bal接种（AIM 3）。粘膜V2抗体是否比全身V2抗体具有任何优势疫苗功效。