HIV-1 mucosal transmission and persistence

HIV-1粘膜传播和持续性

• 批准号: 10116270
• 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/10116270
• 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; virology

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.

项目总结 这个职业生涯中期调查员奖的目标是建立受保护的时间，通过这些时间我可以指导更多的 专注于指导对开展以患者为导向的艾滋病毒-1研究感兴趣的年轻研究人员。我是一个 内科医生接受传染病方面的培训，研究重点是粘膜艾滋病毒-1传播和 坚持不懈。我的职业热情一直是进行以患者为导向的研究，这最终可能 改进疾病的诊断、治疗或预防。在各种活动中获得杰出的指导 我的训练阶段让我成为一名内科研究员，并追求我的激情。我的研究 主要关注被国家卫生研究院视为高度优先领域的主题，并与 病人健康。具体地说，这项提案的目的将阐明艾滋病毒-1粘膜感染的机制， 世界上最常见的传播方式。我的团队已经发现了新的基于上皮的细胞 可能是粘膜暴露后第一个被感染的细胞。R01AI122209和这个奖项将允许我指导 受训人员研究这些独特的上皮细胞如何影响在体内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的情况下重新出现的病毒的来源 停止接受抗逆转录病毒治疗的患者。我也是一名执业临床医生，在临床实践中，它 已经注意到艾滋病毒感染患者的年龄越来越大，大多数患者患有与艾滋病毒相关的非 艾滋病(HANA)状况，如动脉粥样硬化、神经认知能力下降和肾脏病理。一边学习一边学习 已表明全身性炎症与HANA条件有关，持久的机制 在没有外周病毒复制的情况下，炎症状态仍不清楚。R01AG060890以及 该奖项将资助年轻研究人员了解艾滋病毒-1是如何从持续感染的细胞中表达出来的 引发全身炎症。这一认识将为小说的发展提供重要信息 旨在减轻HANA疾病负担的治疗战略。我们还开发了一部小说 抗体依赖的细胞毒性(ADCC)试验，因为这种抗体功能已被认为 在防止传播和减少受感染细胞的持久性方面很重要。R21AI137119将提供资金 ADCC检测方法的优化，优化后的检测方法将用于检测其在预防乳房中的作用 通过减少携带传染性病毒的细胞数量来传播牛奶。K24基金将允许我继续 这些以患者为中心的研究目的，它将增强我培养下一代研究人员的能力， 特别是临床医生科学家，这样他们就可以掌握现代科学方法的技能，对 人类疾病。在这个时候，特别需要未来的临床医生-科学家，因为受过临床培训 医生在临床培训结束后往往不再从事研究。我特别适合做这件事 目标是因为我培训了许多年轻的研究人员，包括临床医生和科学家，他们后来 有独立的研究事业。