Impact of HIV-associated inflammation on disease

简介(申请人提供)：我未来五年的职业目标是(1)招募和指导对艾滋病毒转译研究感兴趣的年轻研究人员，(2)进一步确定长期抗逆转录病毒治疗期间持续炎症的机制和后果，(3)进行旨在减少长期治疗期间艾滋病毒宿主炎症和/或大小的试点临床试验。这些目标将在一个多学科研究计划的背景下实现，该计划旨在将基础研究成果转化为临床研究(“转译研究”)，同时还从具有良好特征的队列中收集生物标本，用于重点实验室研究(通常称为“反向翻译”)。具体地说，L将进行一系列研究，旨在确定艾滋病毒持续存在(在治疗期间)、慢性炎症和终末器官功能之间存在的复杂关系。我还将监督进行一系列研究，旨在减少 炎症和/或蓄水池的大小。这项工作将由一系列赠款资助，包括最近资助的U19，其总体目标是调查在有效治疗期间慢性炎症对艾滋病毒持久性的影响。我正在寻求重新竞争现有的K24。在获得K24助学金之前，我将大约50%的精力投入到临床护理和行政/教学职责上。K24让我专注于指导一系列研究员和初级调查人员，其中许多人现在是独立调查人员。如果成功，我将继续投入约25%的精力指导初级调查人员进行队列开发、转化性研究和临床研究。公共卫生影响：大多数感染艾滋病毒的成年人能够获得抗逆转录病毒治疗，并能够通过现代抗逆转录病毒药物方案实现并维持持久的病毒抑制。尽管有效地抑制了艾滋病毒的复制，但许多患者(如果不是大多数患者)表现出持续性的免疫功能障碍，这反过来可能导致终末器官疾病。此外，现在人们普遍认为，目前的治疗方法并不能治愈，这意味着所有需要治疗的艾滋病毒感染者将不得不继续接受数十年的治疗。这对那些感染艾滋病毒的人来说具有重大的成本和健康影响。因此，旨在减少慢性炎症和/或治愈艾滋病毒的努力将对这两种全球流行病产生长期好处。 公共卫生相关性：更彻底地了解持续性炎症和免疫功能障碍在抗逆转录病毒治疗的成人中导致艾滋病毒持久性和/或疾病中的作用，可能会导致这种疾病的管理发生根本性变化。对炎症对终末器官疾病的影响的洞察甚至可能对理解和处理其他慢性炎症性疾病产生影响。旨在治愈艾滋病毒感染的努力也可能导致在全球一级预防艾滋病毒传播。

DESCRIPTION (provided by applicant): My career objectives over the next five years are (1) to recruit and mentor young investigators interested in translational HIV research, (2) to further define the mechanisms and consequences of persistent inflammation during long-term antiretroviral therapy, and (3) to conduct pilot clinical trials aimed at reducing inflammation and/or size of the HIV reservoir during long-term therapy. These goals will be pursued in the context of a multidisciplinary research program aimed at translating basic research findings into the clinic ("translational research") while also collecting biologic specimens from well characterized cohorts for focused laboratory based research (often referred to as "reverse translation"). Specifically, l will conduct a series of studies aimed at determining the complex relationship that exists between HIV persistence (during therapy), chronic inflammation and end-organ function. I will also oversee the conduct of a series of studies aimed at reducing inflammation and/or size of the reservoirs. This work will be funded by a series of grants, including a recently funded U19 whose overall objectives are to investigate the impact chronic inflammation has on HIV persistence during effective therapy. I am seeking to recompete an existing K24. Prior to receiving this K24 grant, I devoted approximately 50% of total effort to clinical care and administrative/teaching responsibilities. The K24 allowed me to focus on mentoring a series of research fellows and junior investigators, many of whom are now independent investigators. If successful, I will continue to devote approximately 25% of my effort to mentoring junior investigators in the conduct of cohort development, translational research and clinical research. Public health implications: Most HIV infected adults with access to antiretroviral therapy are able to achieve and maintain durable viral suppression with modern antiretroviral drug regimens. Despite effective suppression of HIV replication, many if not most patients exhibit persistent immune dysfunction, which in turn may cause end-organ disease. Also, it is now widely accepted that current therapies are not curative, meaning all HIV infected individuals in need of treatment will have to remain on therapy for many decades. This has significant costs and health implications for those infected with HIV. Efforts aimed at reducing chronic inflammation and/or curing HIV will therefore have long-term benefits for both the global epidemic. PUBLIC HEALTH RELEVANCE: A more thorough understanding of the role of persistent inflammation and immune dysfunction in causing HIV persistence and/or disease in antiretroviral-treated adults could lead to fundamental changes in the management of this disease. Insights into the impact of inflammation on end-organ disease may even have implications for the understanding and management of other chronic inflammatory conditions. Efforts aimed at curing HIV infection could also prove lead to the prevention of HIV transmission on a global level.