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.
Women often lack control over many available behavioral, barrier, and pharmacological HIV prevention measures, underscoring a critical need to enhance their HIV prevention options for women. 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. The proposed research seeks to understand the mucosal immune environment of women and to test the concept that this environment could be modified using a combined anti-viral and anti- inflammatory drug in order to improve PrEP for women.
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