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 这个职业中期调查奖的目标是建立保护的时间，通过它我可以指导更大的 重点是指导有兴趣进行以患者为导向的HIV-1研究的年轻研究人员。我是一个 内科医生接受过传染病方面的培训，研究重点是粘膜HIV-1传播， 坚持不懈我的职业热情一直是进行以病人为导向的研究， 改善疾病的诊断、治疗或预防。在各种培训期间接受杰出的指导 我的训练阶段让我成为一名医生调查员，追求我的激情。我的研究 主要侧重于被美国国立卫生研究院视为高度优先领域的主题， 患者健康。具体而言，该提案的目的将阐明HIV-1粘膜获得的机制， 世界上最常见的传播方式。我的团队已经发现了新的上皮细胞， 可能是粘膜暴露后感染的第一个细胞。R 01 AI 122209，这个奖项将使我能够指导 研究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， 注意到艾滋病毒感染者年龄越来越大，大多数患者患有艾滋病毒相关的非传染性疾病， 艾滋病（HANA）病症，如动脉粥样硬化、神经认知下降和肾脏病理。虽然研究 已经表明，全身性炎症与HANA条件有关，持续性炎症的机制， 在没有外周病毒复制的情况下的炎症状态仍然未知。R 01 AG 060890沿着 该奖项将资助艾滋病研究人员了解HIV-1如何从持续感染的细胞中表达 诱发全身性炎症。这一认识将为开发新型 旨在减轻HANA疾病负担的治疗策略。我们还发明了一种 抗体依赖性细胞毒性（ADCC）测定，因为该抗体功能性已被认为是 在防止传播和减少感染细胞的持久性方面很重要。R21 AI 137119将资助 ADCC测定的优化，并且该优化的测定将用于检查其在预防乳腺癌中的作用。 通过减少携带传染性病毒的细胞数量来减少牛奶传播。K24基金将使我能够 这些以病人为导向的研究目标，它将增强我培养下一代研究人员的能力， 特别是临床科学家，使他们能够获得现代科学方法的技能， 人类疾病在这个时候，有一个特殊的需要，未来的临床科学家，因为临床训练 医生在临床培训后往往不从事研究。我特别适合完成这件事 因为我已经培训了许多年轻的研究人员，包括临床科学家，他们已经去了 有独立的研究生涯。