Impact of Mucosal Immune Enviroment and semen on Prep and PD

项目摘要(见说明)：艾滋病毒主要是性传播的，年轻妇女承担着不成比例的疾病负担。因此，在缺乏有效疫苗的情况下，迫切需要安全有效的暴露前预防(PrEP)。我们假设最佳策略将结合有效的药物，这些药物在多个解剖间隔内有效，表现出快速和持续的药代动力学(PK)，并且是安全的。理想情况下，应该优先考虑持续给药，因为坚持每天或性交依赖的剂量已被证明是困难的。在这些概念的基础上，该计划将重点放在替诺福韦(TFV)前体药物替诺福韦(TDF)或富马酸替诺福韦(TDF)或GS7340与已获许可的CCR5进入抑制剂马拉韦罗(MVC)或有效的非核苷逆转录酶和进入抑制剂IQP-0528的阴道内环(IVR)给药上。我们已经成功地将TDF和IQP-0528从猪尾猴(PTM)的静脉注射中释放出来，并将探索替代TFV前药GS7340的阴道给药，因为它比TFV具有更强的抗病毒活性，在淋巴组织中的分布更好，可能比TDF更稳定。TDF将成为主要的研究药物，因为与TFV相比，TDF具有更强的组织渗透性和效力，良好的安全性，以及我们在PTMS中基于储备库的IVR TDF输送方面的令人兴奋的进展。最近口服和阴道PrEP的临床试验结果相互矛盾，突显了将临床前数据转化为现实应用的困难和复杂性。行为和坚持很可能是导致试验结果不稳定的原因。然而，我们认为，这些不同的结果也有生物学基础。我们假设，与激素成熟的女性相比，青春期女性生殖道粘膜环境可能有所不同，对于性、激素避孕和细菌性阴道病(BV)的反应，女性生殖道粘膜环境可能会发生变化。这些变化调节了药物PK和药效学(PD)，以及艾滋病毒感染的风险，将平衡从保护转移到感染。我们将使用来自美国和非洲成人或青少年受试者的临床样本，在性行为前和性行为后，在开始使用甲羟孕酮(DMPA)避孕之前和之后，以及在BV成功治疗之前和之后，使用新的细胞和组织培养模型来测试这一范式在体外对PK/PD和HIV易感性的影响。我们将评估临床样本对药物渗透性、摄取、代谢和抗病毒活性的影响，并探索导致观察到的变化的机制。结果将促进确定最佳配方，并确定预防艾滋病毒的新战略。

PROJECT SUMMARY (See Instructions): HIV is primarily sexually transmitted with young women bearing a disproportionate burden of disease. Thus, in the absence of an effective vaccine, there is an urgent need for safe and effective pre-exposure prophylaxis (PrEP). We hypothesize that the optimal strategy will combine potent drugs that are active in multiple anatomic compartments, exhibit rapid and sustained pharmacokinetics (PK), and are safe. Ideally, sustained delivery formulations should be prioritized, as adherence to daily or coitally dependent dosing has proven difficult. Building from these concepts, this Program will focus on intravaginal ring (IVR) delivery of tenofovir (TFV) prodrugs, tenofovir disoproxil fumarate (TDF) or GS7340 in combination with maraviroc (MVC), a licensed CCR5 entry inhibitor, or IQP-0528, a potent non-nucleoside reverse transcriptase and entry inhibitor. We have successfully delivered TDF and IQP-0528 from IVRs in pig-tailed macaques (PTM) and will explore vaginal delivery of the alternative TFV prodrug, GS7340, because it has greater antiviral activity than TFV, better distribution into lymphoid tissues and may be more stable than TDF. TDF will be the primary agent of study because of its greater tissue permeability and potency compared to TFV, excellent safety profile and our exciting progress with reservoir-based IVR TDF delivery in PTMs. The conflicting results of recent clinical trials with oral and vaginal PrEP highlight the difficulties and complexities in translating preclinical data into real world use. Behavior and adherence likely contribute to the variable trial results. However, we propose that there is also a biological basis for these disparate outcomes. We hypothesize that the female genital tract mucosal environment, which may differ in adolescents compared to hormonally mature women, is altered in response to sex, hormonal contraception, and bacterial vaginosis (BV). These changes modulate drug PK and pharmacodynamics (PD), as well as the risk of HIV infection, to shift the balance from protection to infection. We will test this paradigm with clinical samples obtained from U.S. and African adult or adolescent subjects pre- and post-sex, prior to and after initiating depot medroxyprogesterone (DMPA) contraception, and before and after successful treatment of BV for their impact on PK/PD and HIV susceptibility ex vivo using novel cell and tissue culture models. We will evaluate the impact of the clinical samples on drug permeability, uptake, metabolism, and antiviral activity and explore the mechanisms that contribute to observed changes. Results will promote the identification of optimal formulations and identify new strategies for HIV prevention.