Characterization and modulation of mucosal immunity for HIV prevention in women

描述(由申请者提供)：有了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调查员，专注于药物预防战略。职业发展计划：我的长期目标是了解女性的粘膜免疫学和药理学，以便开发干预措施，在全球范围内减少艾滋病毒的传播。为了实现这一目标，在K23奖项期间，我将得到一群经验丰富的职业科学家的指导，他们是经验丰富的艾滋病毒转化临床科学家Igho Ofotokun博士，艾滋病毒免疫学家Rama Amara博士，艾滋病毒临床药理学家Ed Acosta博士，以及专注于艾滋病毒和妇女健康的产科/妇科医生Susan Cuu-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室和分析培训。我将带着免疫学和女性生殖道(FGT)抗逆转录病毒药物药理学的综合知识从这个获奖期走出来。与我之前在艾滋病毒感染妇女的临床护理、公共卫生和临床/转化性研究方面的基础相结合，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独树一帜。研究计划：由于妇女往往缺乏对许多可用的艾滋病毒预防措施的控制，如使用避孕套和男性包皮环切术，因此迫切需要加强其艾滋病毒预防选择。在FGT粘膜中，HIV感染的免疫细胞靶点的数量和类型强烈地预测了HIV的易感性。对暴露前预防(PrEP)的研究最近显示了有效性，但在女性中的结果喜忧参半。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降低感染的可能性。潜在靶向FGT独特特性的一种方法是同时给予一种同时发挥抗炎和抗病毒作用的药物，以降低生殖器粘膜靶细胞对艾滋病毒的易感性。马拉韦罗(MVC)是一种抗逆转录病毒药物，可以阻断人CCR5受体，抑制艾滋病毒进入敏感细胞，是测试药物发挥病毒抑制和粘膜免疫调节双重作用的极佳候选药物。我们假设女性有一个动态的粘膜免疫环境，这种环境可以通过MVC的调节来降低粘膜艾滋病毒的风险。我们提出的目标是(1)纵向确定艾滋病毒感染风险女性的生殖器粘膜免疫环境，以及(2)测试MVC可以从药理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细胞激活和炎性细胞因子，以评估生殖器粘膜随时间的变化，并确定生物因素的影响。接下来，我们将按照剂量范围策略在口服MVC的7天疗程之前、期间和之后重复采样，以评估粘膜药物和免疫效果之间的关系，并利用药代动力学/药效学(PK/PD)建模和全球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建模，探索免疫调节的概念，以增强女性的PrEP疗效。在多学科导师团队的支持下，这项研究的完成将使我在专注于女性生物医学艾滋病毒预防干预的独立职业生涯中独一无二地处于有利地位。

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.