Defining Antiretroviral Pharmacology Within HIV-1 Reservoirs of Males and Females

项目总结/摘要 有了这个K23职业发展奖，我将发展必要的技能，以达到我的最终目标， 成为一名独立的研究者，专注于评估艾滋病毒治愈的药理学障碍。 职业发展计划：我的长期目标是成为一名独立资助的研究人员， 临床药理学和药代动力学（PK）-药效学（PD）建模方面的专业知识，为未来的研究提供信息 艾滋病毒治疗战略。在K23期间的短期内，我的目标是研究抗逆转录病毒（ARV） 药物暴露和HIV宿主内的病毒动态关系，并优先考虑性探索 这些关系中的差异。为了实现这些目标，我将在K23颁奖期间接受指导 一群经验丰富的职业科学家：Igho Ofotokun博士，一位艾滋病毒转化临床科学家 艾滋病临床药理学家爱德华·阿科斯塔博士和雷蒙德博士 Schinazi是新药开发和艾滋病治疗领域的翻译科学家。贯穿本 在职业奖励期间，我将完成基础实验药理学的课程和实践培训， 纵向生物统计分析、PK-PD建模、性和性别科学、艾滋病毒治愈/根除，以及 科学沟通。结合我以前在艾滋病毒感染者临床护理方面的基础， 人，在临床研究和临床/转化研究科学硕士，这种培训将独特的 定位我在HIV治疗策略中的临床药理学应用的独立职业生涯。 研究计划：新出现的证据表明，血浆以外的部位，如外周血， 单核细胞（PBMC）和肠道相关淋巴组织仍然是HIV的储存库， 尽管长期有效的联合抗逆转录病毒治疗（cART），病毒持续存在的作用。次优ARV 这些储存库中的药物浓度被认为是导致我们无法完全根除艾滋病毒的原因。在 此外，已发现宿主因素如性别影响这些部位内的抗逆转录病毒药物暴露和效果。 关键结果，如病毒学抑制时间。我们对储库部位药理学的了解， 对性别的影响是有限的，这是由于以下几个障碍：1）难以对水库进行密集采样; 2） 参加艾滋病毒临床研究的妇女很少。理想的药物浓度是 在药物开发早期通过需要密集血浆采样的剂量范围研究确定; 这种方法在组织部位内使用是不切实际的。为了减少这些障碍，我们建议研究 整合酶链转移抑制剂度鲁特韦（DTG）在三个身体隔室中的药理学： 血浆、PBMC和直肠组织，使用新的整合群体药代动力学-病毒动力学 （PK-VD）建模方法。该PK-VD建模策略生成浓度-响应关系 有限的采样和定量模拟非常适合水库现场。此外，我们将优先考虑 探索性别差异，利用我们广泛的研究基础设施，包括临床核心 埃默里艾滋病研究中心（CFAR），亚特兰大临床和转化科学研究所（ACTSI）， 亚特兰大妇女跨部门艾滋病研究（WIHS）的动机队列。我们假设 综合群体PK-VD模型将显示，抑制HIV所需的最佳药物剂量将更高， 与血浆相比，PBMC和直肠组织储库中的差异在雄性和 女性我们提出的目的是：1）比较DTG PK-VD血液产生的描述性数据 血浆模型对现有剂量范围研究数据进行验证，2）扩展DTG PK-VD的开发 PBMC和直肠组织储库模型，以及3）研究所有三种模型中DTG PK-VD的性别差异 身体部位。为了实现这一目标，20名未接受过抗逆转录病毒治疗的艾滋病毒感染男性和20名未接受过抗逆转录病毒治疗的艾滋病毒感染女性 （总共n = 40）将入组84天（12周）纵向研究， 将在7次研究访视期间连续采集直肠组织样本，以测量DTG浓度、HIV-1 RNA 病毒载量和2-LTR未整合的HIV DNA环。根据这些数据，综合群体PK-VD模型将 构建并使用剂量模拟来确定获得病毒学所需的最佳药物暴露 在雄性和雌性中的所有三个位点均抑制。在多学科导师团队的支持下， 这项工作的完成将使我成为一个独立的研究职业， 艾滋病毒治疗战略中的干预措施。

PROJECT SUMMARY/ABSTRACT With this K23 Career Development Award, I will develop the skills necessary to reach my ultimate goal of becoming an independent investigator focused on assessing pharmacologic barriers to HIV cure. Career Development Plan: My long-term goal is to become an independently funded researcher with expertise in clinical pharmacology and pharmacokinetic (PK)-pharmacodynamic (PD) modeling to inform future HIV cure strategies. In the short-term during this K23 period, my goals are to investigate antiretroviral (ARV) drug exposure and viral dynamic relationships within HIV reservoirs and to prioritize exploration of sex differences within these relationships. In order to attain these goals, I will be mentored during this K23 award period by a group of experienced career scientists: Dr. Igho Ofotokun, an HIV translational clinician scientist with a focus on women's health, Dr. Edward Acosta, an HIV clinical pharmacologist, and Dr. Raymond Schinazi, a translational scientist in the arenas of novel drug development and HIV cure. Throughout this career award period, I will complete coursework and hands-on training in basic experimental pharmacology, longitudinal biostatistical analyses, PK-PD modeling, sex and gender sciences, HIV cure/eradication, and scientific communication. In combination with my previous foundation in the clinical care of HIV-infected persons, Master of Science in Clinical Research, and clinical/translational research, this training will uniquely position me for an independent career in the application of clinical pharmacology within HIV cure strategies. Research Plan: Emerging evidence indicates that sites outside of blood plasma, such as peripheral blood mononuclear cells (PBMCs) and gut-associated lymphoid tissue, remain reservoirs for HIV and play critical roles in viral persistence despite long-term potent combination antiretroviral therapy (cART). Suboptimal ARV drug concentrations within these reservoirs are thought to contribute to our inability to fully eradicate HIV. In addition, host factors such as sex have been found to impact ARV drug exposure within these sites and effect key outcomes such as time to virologic suppression. Our understanding of reservoir site pharmacology and the impact on sex is limited due to several barriers: 1) Difficulty in sampling reservoir sites intensively and 2) Scarcity of women enrolled in HIV clinical research studies. Optimal drug concentrations are ideally determined early in drug development by dose-ranging studies that require intensive blood plasma sampling; this methodology is impractical to employ within tissue sites. To mitigate these barriers, we propose to study the pharmacology of the integrase strand transfer inhibitor dolutegravir (DTG) within three body compartments: blood plasma, PBMCs, and rectal tissue using a novel integrated population pharmacokinetic-viral dynamic (PK-VD) modeling approach. This PK-VD modeling strategy generates concentration-response relationships with limited sampling and dosing simulations ideally suited to reservoir sites. Additionally, we will prioritize the exploration of sex differences by leveraging our extensive research infrastructure, including the clinical core of the Emory Center for AIDS Research (CFAR), the Atlanta Clinical and Translational Science Institute (ACTSI), and the motivated cohort of the Atlanta Women's Interagency HIV Study (WIHS). We hypothesize that integrated population PK-VD modeling will show that optimal drug doses needed to suppress HIV will be higher in PBMC and rectal tissue reservoirs compared to blood plasma and will be different between males and females. Our proposed aims are: 1) Compare descriptive data generated from our DTG PK-VD blood plasma model to existing dose-ranging study data for validation, 2) Extend the development of DTG PK-VD models to PBMC and rectal tissue reservoirs, and 3) Investigate sex differences in DTG PK-VD in all three body sites. To accomplish this, 20 ARV-naïve HIV-infected males and 20 ARV-naïve HIV infected females (total n = 40) will be enrolled in an 84 day (12 week) longitudinal study whereby blood plasma, PBMCs, and rectal tissue will be serially sampled during seven (7) study visits to measure DTG concentrations, HIV-1 RNA viral load, and 2-LTR unintegrated HIV DNA circles. From these data, integrated population PK-VD models will be constructed and dosing simulations used to determine optimal drug exposure needed to attain virologic suppression at all three sites within males and females. With support from a multi-disciplinary team of mentors, completion of this work will uniquely position me for an independent research career integrating pharmacologic interventions within HIV cure stratagems.