HIV-1 mucosal transmission and persistence

HIV-1粘膜传播和持续性

• 批准号: 10355517
• 负责人: Manish Sagar
• 金额: $ 18.17万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355517
• 关键词: AIDS prevention; Aging; Anti-Retroviral Agents; Antibodies; Area; Atherosclerosis; Award; Biological Assay; Caring; Cells; Clinical; Collaborations; Communicable Diseases; Dendritic Cells; Development; Diagnosis; Diagnostic; Disease; Epithelial; Epithelial Cells; Fostering; Frequencies; Funding; Future; Goals; HIV; HIV-1; Health; Heart Diseases; Human Milk; Immune; Individual; Infection; Inflammation; Inflammatory; Internist; Kidney; Laboratories; Link; Lymphocyte; Mentors; Methods; Mid-Career Clinical Scientist Award (K24); Modernization; Morbidity - disease rate; Mucous Membrane; Myeloid Cells; Neurocognitive Deficit; Pathology; Patients; Peripheral; Physicians; Plasma; Principal Investigator; Research; Research Personnel; Research Project Grants; Role; Scientist; Secure; Source; Systemic infection; Time; Tissues; Training; United States National Institutes of Health; Vagina; Virus; Virus Replication; Work; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; career; clinical practice; clinically relevant; disorder prevention; human disease; improved; interest; next generation; novel; novel therapeutic intervention; patient oriented; patient oriented research; post-doctoral training; prevent; response; senescence; skills; systemic inflammatory response; transmission process

PROJECT SUMMARY The goal of this midcareer investigator award is to establish protected time through which I can direct greater focus towards mentoring young investigators interested in conducting patient oriented HIV-1 research. I am an internist trained in infectious disease with research that focuses on mucosal HIV-1 transmission and persistence. My career passion has always been to conduct patient oriented research that may ultimately improve diagnostics, treatment, or prevention of disease. Receipt of outstanding mentoring during various stages of my training allowed me to become a physician investigator and pursue my passion. My research primarily focuses on topics deemed high priority areas by the National Institutes of Health and relevant for patient health. Specifically, aims of this proposal will elucidate mechanisms for HIV-1 mucosal acquisition, the most common mode of transmission in the world. My group has identified novel epithelial-based cells that are potentially the first cell infected after mucosal exposure. R01AI122209 and this award will allow me to mentor trainees in examining how these unique epithelial cells impact the types of virus that establish infection in exposed hosts and how these cells can be source of the virus that re-emerges among virologically suppressed patients that stop taking antiretroviral therapy. I am also a practicing clinician, and in clinical practice, it has been noted that HIV infected patients are getting older and majority of patients suffer from HIV associated non AIDS (HANA) conditions, such as atherosclerosis, neurocognitive decline, and renal pathology. While studies have shown that systemic inflammation associates with HANA conditions, mechanisms for persistent inflammatory state in the absence of peripheral virus replication remain unknown. R01AG060890 along with this award will fund young-investigators to understand how HIV-1 expression from persistently infected cells induces systemic inflammation. This understanding will provide important information for developing novel therapeutic strategies aimed at ameliorating the burden of HANA diseases. We have also developed a novel antibody dependent cellular cytotoxicity (ADCC) assay because this antibody functionality has been deemed important in preventing transmission and decreasing the persistence of infected cells. R21AI137119 will fund optimization of the ADCC assay, and this optimized assay will be used to examine its role in preventing breast milk transmission by reducing the number of cells harboring infectious virus. K24 funds will allow me to pursue these patient oriented research aims, and it will augment my ability to train the next generation of researchers, especially clinician-scientists, so that they may gain skills in modern scientific methods to make an impact on human disease. At this time, there is a special need for future clinician-scientists because clinically trained physicians are often not pursuing research after their clinical training. I am particularly suited to accomplish this goal because I have trained numerous young investigators, including clinician-scientists, who have gone on to have independent research careers.

项目摘要 这个中级研究员奖的目标是建立受保护的时间，我可以指导更多 专注于指导有兴趣进行以患者为导向的HIV-1研究的年轻研究者。我是一个 接受了从事传染病培训的Internist，研究着重于粘膜HIV-1传播和 持久性。我的职业热情一直是进行以患者为导向的研究 改善诊断，治疗或预防疾病。在各种期间收到杰出的指导 我的培训阶段使我成为一名医师调查员并追求自己的激情。我的研究 主要关注美国国立卫生研究院认为高优先级领域的主题，并与之相关 患者健康。具体而言，该提案的目的将阐明HIV-1粘膜获取的机制，即 世界上最常见的传播方式。我的小组已经确定了新型的基于上皮的细胞 可能是粘膜暴露后感染的第一个细胞。 R01AI122209和该奖项将使我能够指导 学员检查了这些独特的上皮细胞如何影响建立感染的病毒类型 暴露的宿主以及这些细胞如何成为在病毒学抑制中重新出现的病毒的来源 停止接受抗逆转录病毒疗法的患者。我也是一名执业临床医生，在临床实践中，它具有 人们注意到，受艾滋病毒感染的患者年龄较大，大多数患者患有艾滋病毒相关的非艾滋病毒 艾滋病（HANA）疾病，例如动脉粥样硬化，神经认知能力下降和肾脏病理。研究 已经表明，系统性炎症与HANA条件，持续的机制相关 在没有外周病毒复制的情况下，炎症状态仍然未知。 R01AG060890以及 该奖项将资助年轻评估者，以了解HIV-1如何表达来自感染细胞的持续感染细胞 引起全身炎症。这种理解将为发展小说提供重要信息 旨在减轻HANA疾病负担的治疗策略。我们还开发了一本小说 抗体依赖性细胞毒性（ADCC）测定法，因为该抗体功能已被视为 对于防止传播和减少感染细胞的持久性很重要。 R21AI137119将资助 ADCC测定的优化，该优化测定将用于检查其在防止乳房中的作用 通过减少具有感染性病毒的细胞数量来传播牛奶。 K24资金可以让我追求 这些面向患者的研究的目的，它将增强我培训下一代研究人员的能力， 特别是临床医生科学家，以便他们可以获得现代科学方法的技能，以影响 人类疾病。目前，未来的临床医生有特别的需求，因为经过临床培训 医师在临床培训后通常不会进行研究。我特别适合实现这一目标 目标是因为我训练了许多年轻的调查员，包括临床医生， 有独立的研究职业。