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.

项目概要 这个职业生涯中期调查员奖的目标是建立受保护的时间，通过它我可以指导更多的工作 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 受过传染病培训的内科医生，其研究重点是粘膜 HIV-1 传播和 坚持。我的职业热情一直是进行以患者为导向的研究，最终可能 改善疾病的诊断、治疗或预防。在不同的时期受到杰出的指导 我的培训阶段使我成为一名医师调查员并追求我的激情。我的研究 主要关注美国国立卫生研究院认为高度优先领域并与以下领域相关的主题 患者健康。具体来说，该提案的目的将阐明 HIV-1 粘膜获得的机制，即 世界上最常见的传播方式。我的小组已经鉴定出新型上皮细胞 可能是粘膜暴露后第一个被感染的细胞。 R01AI122209 这个奖项将让我能够指导 受训者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中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， 值得注意的是，艾滋病毒感染者正在变老，并且大多数患者患有与艾滋病毒相关的非 艾滋病 (HANA) 病症，例如动脉粥样硬化、神经认知能力下降和肾脏病理。学习期间 已经表明，全身炎症与 HANA 状况、持久性机制相关 在没有外周病毒复制的情况下炎症状态仍然未知。 R01AG060890 以及 该奖项将资助年轻研究人员了解持续感染细胞中 HIV-1 的表达方式 诱发全身炎症。这种理解将为开发新颖的技术提供重要信息。 旨在减轻 HANA 疾病负担的治疗策略。我们还开发了小说 抗体依赖性细胞毒性（ADCC）测定，因为这种抗体功能已被认为 对于防止传播和减少受感染细胞的持续存在很重要。 R21AI137119将资助 ADCC 检测的优化，该优化的检测将用于检验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进行乳汁传播。 K24基金将让我能够追求 这些以患者为导向的研究目标，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，从而对 人类疾病。此时，特别需要未来的临床医生科学家，因为经过临床培训 医生在接受临床培训后通常不会进行研究。我特别适合完成这个任务 目标，因为我培训了许多年轻的研究人员，包括临床医生科学家，他们已经继续 有独立的研究生涯。