Understanding the mechanism(s) of systemic antibody delivery, distribution, and localization to mucosal sites in the in vivo macaque model

了解体内猕猴模型中全身抗体递送、分布和粘膜部位定位的机制

• 批准号: 9981491
• 负责人: Ann M Carias
• 金额: $ 33.59万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981491
• 关键词: AIDS prevention; Anatomy; Animals; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antibody-mediated protection; Area; Autoimmune Diseases; Award; Basic Science; Binding; Blood - brain barrier anatomy; Blood Circulation; Brain; Cells; Cessation of life; Clinical Trials; Data; Development; Drug or chemical Tissue Distribution; Epithelial; Epithelial Cells; Epithelium; Epitopes; Evaluation; Event; Explosion; Foundations; Future; Gene Expression; Generations; Grant; Growth and Development function; Gut Mucosa; HIV; HIV Infections; HIV vaccine; Human; Immunoglobulin Somatic Hypermutation; Immunoglobulin binding proteins; In Vitro; Infection; Infusion procedures; Injections; Intervention; Investments; Knowledge; Label; Light; Macaca; Macaca mulatta; Mentorship; Microscopy; Modeling; Modification; Monoclonal Antibodies; Movement; Mucous Membrane; Mutation; Organ; Passive Transfer of Immunity; Pathogenesis; Pathway interactions; Patients; Positron-Emission Tomography; Prevention; Primates; Protein Isoforms; Research; Research Personnel; SIV; Site; Squamous Epithelium; Stratum corneum; Systemic infection; Techniques; Therapeutic; Therapeutic Uses; Therapeutic antibodies; Time; Tissues; Vaccines; Vagina; Validation; Work; base; cancer therapy; career development; cell type; clinical application; cost; design; efficacy evaluation; imaging modality; in vivo; insight; interest; mucosal site; neutralizing antibody; nonhuman primate; novel; particle; prevent; rectal; simian human immunodeficiency virus; training opportunity; transmission process; two photon microscopy; vaccine development; vaginal mucosa

To date, although the number HIV-related deaths are on the decline due to antiretroviral and other biomedical interventions, there is still a vaccine lacking for HIV. Recently, there has been increased interest in the utilization of broadly neutralizing antibodies (bNAbs) as a vaccine strategy, which have been illustrated to bind and inactivate lentiviral particles in non-human primate models. Not only have bNAb passive transfer studies in rhesus macaques demonstrated protection against lentiviral infection, but have also led to the first bNAb human clinical trial, the Antibody Mediated Protection (AMP) study. Although these are valiant efforts towards blocking HIV infection, it is still unknown how these antibodies are delivered to mucosal sites where HIV transmission occurs. Gaining a better understanding of how these antibodies are anatomically distributed will have a great impact in the effort to develop a vaccine to prevent HIV acquisition. In order to accomplish this objective, I have been working to develop a novel platform to track fluorescently labeled antibodies in the in vivo rhesus macaque model. To date, utilizing this technique, I have revealed that antibodies take approximately one week to reach a steady state after infusion — an observation that could have implications for the ongoing AMP trial. Additionally, I have observed unique bNAb localization within tissue resident cells in those areas important in HIV transmission and pathogenesis, such as the rectal and vaginal mucosa, and brain. Based on these preliminary data, I propose in Aim 1 to identify the mechanisms of antibody transport and localization using the in vivo nonhuman primate model. In Aim 2, I will characterize the mechanism(s) of antibody association with specific, tissue resident cells at distinct anatomical sites after systemic application. Finally, in Aim 3, I will use the data from the first two aims to determine if antibody subclass influences tissue transport and localization. Overall, this award is integral to the completion of these aims in understanding the foundation of the mechanistic, basic science behind antibody distribution and localization events. With this opportunity, combined with the mentorship provided by Dr. Thomas Hope and Dr. Ronald Veazey, I can start to unravel the complexities of how protective antibodies are delivered to those sites involved in HIV transmission and pathogenesis. This knowledge is critical to advance the effort in the development of a vaccine that is able to provide protection from HIV infection, especially at mucosal sites. Additionally, the training opportunities to elucidate these mechanisms are extremely valuable to my development as a researcher, as it will also provide me with an important skillset and future experimentation that I can carry forward to academic independence.

迄今为止，尽管由于抗逆转录病毒和其他生物医学治疗，与艾滋病毒有关的死亡人数正在下降