Next Generation Pre-exposure Prophylaxis

描述（由申请人提供）：粘膜HIV暴露是全球绝大多数HIV-1感染的原因。具体来说，阴道性交是最常见的艾滋病毒传播方式。因此，预防性传播是当务之急。尽管CAPRISA 004试验的结果非常令人鼓舞，但很明显，观察到的保护水平不是最佳的，还有进一步改进的显著空间。此外，正在进行的暴露前预防（PrEP）随机临床试验中（单独或联合）使用的化学预防药物替诺福韦（Tenofovir）也被广泛用作艾滋病毒感染的一线治疗。在该提案中，我们将默克和UNC的四位杰出研究人员的优势与高度互补的技能结合起来，使用高度创新的方法来解决对下一代PrEP药物开发至关重要的问题。具体而言，1)由默克公司Daria Hazuda开发的新型第二代整合酶抑制剂（MK-2048），尚未用于治疗或PrEP，并且具有不同于其他整合酶抑制剂的耐药谱；2)在UNC，由J. Victor Garcia开发的高度创新的粘膜HIV传播体内模型将首次利用无细胞和细胞相关的原代传播/创始人（F/T）病毒在精液存在下进行挑战；3) UNC Angela Kashuba开发的最先进的分析方法，用于测定阴道应用的MK-2048的PD/PK，以建立体内保护的相关性；4)由UNC的Russ Mumper开发的黏着凝胶制剂和阴道内环，用于优化MK-2048的释放，能够穿透女性生殖道组织，建立有效的药理屏障。为了实现这些目标，我们提出了以下具体目标：具体目标1)为新一代PrEP药物的开发和体内试验建立基础和临床前框架。2)开发用于阴道给药的整合酶抑制剂MK- 2048的水基黏附凝胶制剂。3)在人源化BLT小鼠中进行MK-2048的概念安全性和有效性验证研究。4)建立药代动力学-药效学（PK-PD）模型，评价MK-2048对人源化BLT小鼠雌性生殖道的保护作用。

DESCRIPTION (provided by applicant): Mucosal HIV exposures are responsible for the vast majority of HIV-1 infections worldwide. Specifically, vaginal intercourse is the most common form of HIV transmission. Therefore, prevention of sexual transmission is urgently needed. Despite the highly encouraging results from the CAPRISA 004 trial it is clear that the level of protection observed is suboptimal and that there is significant room for further improvement. In addition, Tenofovir, the chemo-prophylactive agent being used (alone or in combination) in ongoing randomized clinical trials of pre-exposure prophylaxis (PrEP) is also being widely used as front line therapy for HIV infection. In this proposal we combine the strengths of four outstanding investigators at Merck and UNC with highly complementary skills to address, using highly innovative approaches, issues of fundamental importance to the development of the next generation of PrEP agents. Specifically, 1) a novel second generation integrase inhibitor (MK-2048) developed by Daria Hazuda at Merck that has not been used for treatment or for PrEP and that has a resistance profile that is different from other integrase inhibitors; 2) at UNC, a highly innovative in vivo model of mucosal HIV transmission developed by J. Victor Garcia that will for the first time utilize cell free and cell associated primary transmitted/founder (F/T) viruses for challenge in the presence of semen; 3) state-of-the-art analytical methods developed by Angela Kashuba at UNC to determine the PD/PK of vaginally applied MK-2048 to establish correlates of in vivo protection; and 4) mucoadhesive gel formulations and intravaginal rings developed by Russ Mumper at UNC for the optimized release of MK-2048 capable of penetrating the tissues of the female reproductive tract to establish an effective pharmacological barrier. In order to attain these goals we propose the following specific aims: Specific Aim 1) To develop the basic and preclinical framework for the development and in vivo testing of new generations of PrEP agents. Specific Aim 2) To develop aqueous-based mucoadhesive gel formulations of the integrase inhibitor MK- 2048 for vaginal administration. Specific Aim 3) To conduct proof-of-concept safety and efficacy studies of MK-2048 in humanized BLT mice. Specific Aim 4) To generate pharmacokinetic-pharmacodynamic (PK-PD) models to assess the protective effect of MK-2048 in the female reproductive tract of humanized BLT mice.