Next Generation Pre-exposure Prophylaxis

描述（由申请人提供）：粘多糖HIV暴露是全球绝大多数HIV-1感染的原因。具体来说，阴道性交是艾滋病毒传播的最常见形式。因此，迫切需要预防性传播。尽管CAPRISA 004试验的结果非常令人鼓舞，但很明显，观察到的保护水平并不理想，还有很大的进一步改进余地。此外，替诺福韦，正在进行的暴露前预防（PrEP）随机临床试验中使用（单独或组合）的化学治疗活性剂，也被广泛用作HIV感染的一线治疗。 在本提案中，我们将联合收割机与默克公司的四位杰出研究人员的优势相结合，并利用高度创新的方法，以解决对下一代PrEP药物开发至关重要的问题。具体地，1）由Merck的Daria Hazuda开发的新型第二代整合酶抑制剂（MK-2048），其尚未用于治疗或用于PrEP，并且具有不同于其它整合酶抑制剂的抗性特征; 2）在100 ℃时，由J.维克托加西亚开发的粘膜HIV传播的高度创新的体内模型，其将首次利用无细胞和细胞相关的原代细胞，3）Angela Kashuba在ESTA开发的最先进的分析方法，用于确定阴道应用MK-2048的PD/PK，以建立体内保护的相关性;和4）粘膜粘附凝胶制剂和阴道环，其由Russ Mumper在1998年开发，用于MK-1的优化释放。2048能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试剂的开发和体内测试开发基本和临床前框架。具体目的2）开发用于阴道给药的整合酶抑制剂MK- 2048的水基粘膜粘附凝胶制剂。具体目的3）在人源化BLT小鼠中进行MK-2048的概念验证安全性和有效性研究。具体目的4）生成药代动力学-药效学（PK-PD）模型，以评估MK-2048在人源化BLT小鼠雌性生殖道中的保护作用。

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.