Characterization and modulation of mucosal immunity for HIV prevention in women

描述（由申请人提供）：凭借K23职业发展奖，我将发展技能，以实现我的最终目标，成为艾滋病毒和妇女健康领域的独立研究者，重点是药物预防策略。职业发展规划：我的长期目标是了解女性的粘膜免疫学和药理学，以便制定干预措施，以减少全球艾滋病毒的传播。为了实现这一目标，我将在K23奖期间接受一组经验丰富的职业科学家的指导：经验丰富的HIV转化临床科学家Igho Ofotokun博士、基础科学HIV免疫学家Rama Amara博士、HIV临床药理学家Ed Acosta博士和专注于HIV和妇女健康的妇产科医生Susan Cu-Uvin博士。作为培训的一部分，我将完成纵向数据分析、基础免疫学和临床药理学方面的高级课程，并接受免疫学和药理学方面的动手实验和分析培训。我将在这个奖项期间对女性生殖道（FGT）的免疫学和抗逆转录病毒药物药理学有一个全面的了解。结合我之前在艾滋病毒感染妇女的临床护理、公共卫生和临床/转化研究方面的基础，这次培训将使我在艾滋病毒和妇女健康领域的独立研究生涯中处于独特的地位。研究计划：由于妇女往往无法控制许多现有的艾滋病毒预防措施，如使用避孕套和男性包皮环切，因此迫切需要加强她们的艾滋病毒预防选择。在FGT粘膜中，HIV感染的免疫细胞靶点的数量和类型强烈预测HIV易感性。暴露前预防（PrEP）是一种艾滋病毒预防策略，在潜在的艾滋病毒暴露之前使用抗逆转录病毒药物以减少感染的可能性。最近，对暴露前预防（PrEP）的研究显示出效果，但在妇女中的结果好坏参半。一种潜在靶向FGT独特特性的方法是同时施用一种具有抗炎和抗病毒作用的药物，以降低生殖器粘膜靶细胞的HIV易感性。Maraviroc （MVC）是一种阻断人类CCR5受体并抑制HIV进入易感细胞的抗逆转录病毒药物，是测试一种药物发挥病毒抑制和粘膜免疫调节双重作用的潜力的极好候选者。我们假设女性有一个动态的粘膜免疫环境，可以通过MVC来调节，以降低粘膜HIV风险。我们提出的目标是：(1)纵向定义艾滋病毒感染风险妇女的生殖器粘膜免疫环境；(2)测试可以用MVC从药理学上改变生殖器免疫环境的概念。首先，我们将在三个月经周期内每周收集HIV高危妇女的生殖道和全血样本，以测量HIV靶细胞、t细胞活化和炎症细胞因子，以评估生殖器粘膜如何随时间变化并确定生物因素的影响。接下来，我们将在7天口服MVC之前、期间和之后重复采样，以剂量范围策略评估粘膜药物与免疫效应之间的关系，并利用药代动力学/药效学（PK/PD）模型和全局基因表达分析探索潜在的机制。通过完成这些目标，我将结合最先进的实验室技术和创新的PK/ PD模型来探索免疫调节的概念，以提高女性PrEP的疗效。在多学科导师团队的支持下，这项研究的完成将使我成为一个专注于女性生物医学艾滋病毒预防干预的独立职业。

DESCRIPTION (provided by applicant): With the K23 Career Development Award, I will develop the skills to reach my ultimate goal of becoming an independent investigator in the field of HIV and women's health with a focus on pharmaco-prevention strategies. Career Development Plan: My long-term goal is to understand mucosal immunology and pharmacology in women in order to develop interventions to reduce HIV transmission globally. In order to attain this goal, I will be mentored during the K23 award period by a team of experienced career scientists: Dr. Igho Ofotokun, an experienced HIV translational clinician scientist, Dr. Rama Amara, a basic science HIV immunologist, Dr. Ed Acosta, an HIV clinical pharmacologist, and Dr. Susan Cu-Uvin, an obstetrician/gynecologist with a focus on HIV and women's health. As part of my training, I will complete advanced coursework in longitudinal data analysis, basic immunology, and clinical pharmacology and receive hands-on laboratory and analytic training in both immunology and pharmacology. I will emerge from this award period with an integrated knowledge of immunology and antiretroviral drug pharmacology in the female genital tract (FGT). In combination with my previous foundation in clinical care of HIV-infected women, public health, and clinical/translational research, this training will uniquely position me for an independent research career in the area of HIV and women's health. Research Plan: Because women often lack control over many available HIV prevention measures such as condom use and male circumcision, there is a critical need to enhance their HIV prevention options. In the FGT mucosa, the number and type of immune cellular targets for HIV infection strongly predicts HIV susceptibility. Studies examining pre-exposure prophylaxis (PrEP), an HIV prevention strategy in which antiretroviral drugs are used prior to potential HIV exposure to reduce the likelihood of infection, have recently shown efficacy, but results in women have been mixed. One way to potentially target the unique properties of the FGT is to simultaneously administer a drug that exerts both anti-inflammatory and antiviral effects to reduce HIV susceptibility of genital mucosal target cells. Maraviroc (MVC), an antiretroviral drug that blocks the human CCR5 receptor and inhibits HIV entry into susceptible cells, is an excellent candidate for testing a drug's potential of exerting the dual action of viral inhibition and mucosal immune modulation. We hypothesize that women have a dynamic mucosal immune environment that can be modulated with MVC in a manner to reduce mucosal HIV risk. Our proposed aims are (1) to longitudinally define the genital mucosal immunologic environment in women at risk for HIV infection and (2) to test the concept that the genital immune environment can be pharmacologically modified with MVC. First, we will collect genital tract and whole blood samples from HIV at-risk women weekly over three menstrual cycles to measure HIV target cells, T-cell activation, and inflammatory cytokines to assess how the genital mucosa changes over time and define the impact of biologic factors. Next, we will repeat sampling before, during, and after a 7-day course of oral MVC given in a dose- ranging strategy to assess the relationship between mucosal drug and immunologic effects and explore potential mechanisms using pharmacokinetic/ pharmacodynamics (PK/PD) modeling and global gene expression analyses. Through completion of these aims, I will integrate state-of-the-art laboratory techniques and innovative PK/ PD modeling to explore the concept of immune modulation to enhance PrEP efficacy in women. In conjunction with support from a multidisciplinary team of mentors, completion of this research will uniquely position me for an independent career focused on biomedical HIV prevention interventions for women.