Bioresponsive Combination Microbicide Delivery System for HIV and HSV

说明（由申请人提供）：全世界有4 200多万艾滋病毒感染者，艾滋病毒感染仍然是一个重大的健康问题。值得注意的是，妇女占受感染人口的近一半，在世界许多地区，艾滋病毒感染率惊人且不断上升。这促使研究人员开发预防措施，用一种叫做杀微生物剂的药剂来减缓或阻止艾滋病毒在男性和女性之间的性传播。此外，艾滋病毒的性传播往往受到其他因素的帮助。来自30多项流行病学研究的数据表明，2型单纯疱疹病毒（HSV-2）感染与获得HIV-1的风险增加约2至4倍有关。由于普通人群中普遍存在2型单纯疱疹病毒，我们认识到这是艾滋病毒传播的一个重要加剧因素。该项目的总体目标是开发和优化一种多功能联合杀微生物剂，即使在2型单纯疱疹病毒高流行人群中也能安全有效地预防艾滋病毒传播。我们将在一种模仿HSV感染人类的HIV传播的SHIV恒河猴模型中评估这种候选杀微生物剂的安全性和有效性。在第一年和第二年，我们将同时努力实现两个互补但独立的目标。第一个目标是设计和配制一种生物反应性组合杀菌剂，该杀菌剂由自组装凝胶组成，该凝胶在阴道pH值为半固体，在精液pH值为液化。凝胶将装载抗病毒核苷抑制剂替诺福韦（TNFV）和阿昔洛韦（ACV），以及病毒中和剂CAP（醋酸邻苯二甲酸纤维素）。在体外和体内测试凝胶的释放率、抗病毒活性和毒性。根据这些数据，将确定两种主要配方。第二个目标是开发和验证猿猴艾滋病毒（模仿人类艾滋病毒感染的灵长类动物模型中的SHIV感染）。为了解决抗hiv杀菌剂在HSV感染高发人群中的有效性，我们将在病毒共感染灵长类动物模型中测试联合杀菌剂。我们将首先在猕猴体内建立并验证SHIV和HSV剂量，从而产生病毒脱落和疾病发展。在R33期，该灵长类动物模型将用于评估最有希望的含有病毒中和剂（CAP）和抗病毒药物（TNFV和ACV）的杀微生物剂配方在最大程度上防止HIV传播方面的有效性和安全性。计划在3-5年进行的这类实验将确定提供最大限度防止艾滋病毒传播保护的剂量反应、剂量频率和剂量持续时间。

DESCRIPTION (provided by applicant): With more than 42 million HIV-infected individuals worldwide, HIV infection continues to be a significant health problem. Notably, women comprise nearly half of the infected population, with a staggering and increasing rate of HIV infection in many regions of the world. This has spurred researchers to develop preventative measures to slow or stop the male to female sexual transmission of HIV with agents called microbicides. Moreover, the sexual transmission of HIV is often aided by the presence of other factors. Data from more than 30 epidemiological studies indicate that herpes simplex virus type-2 (HSV-2) infection is associated with about a two- to four-fold increase in the risk of HIV-1 acquisition. Due to the prevalence of HSV-2 in the general population, we recognize this as a significant aggravating factor for the transmission of HIV. The overall goal for the project is to develop and optimize a multifunctional combination microbicide that is safe and effective in preventing HIV transmission even in populations with high HSV-2 prevalence. We will evaluate the safety and efficacy of this candidate microbicide in a SHIV rhesus macaque model that mimics HIV transmission in HSV infected humans. In year 1 and 2, there are two complementary yet independent goals that we will work toward simultaneously. The first goal is to design and formulate a bioresponsive combination microbicide composed of a self- assembling gel that is a semisolid at vaginal pH and liquefies at seminal pH. The gels will be loaded with the antiviral nucleoside inhibitors Tenofovir (TNFV) and Acyclovir (ACV), and a viral neutralizing agent CAP (cellulose acetate phthalate). The gels will be tested for release rate, antiviral activity and toxicity in vitro and in vivo. From this data, two lead formulations will be identified. The second goal is to develop and validate a simian HIV (SHIV infection in a primate model that mimics HIV infection in humans). To address the effectiveness of an anti-HIV microbicide in a population with high incidence of HSV infection, we will test the combination microbicide in a viral co-infection primate model. We will first establish and validate a SHIV and HSV dose in macaques that produces virus shedding and disease development. In R33 phase, this primate model will be used to evaluate efficacy and safety of the most promising microbicide formulation containing virus neutralization agent (CAP) and antiviral (TNFV and ACV) in providing maximum protection against HIV transmission. Such experiments, planned for years 3-5 will determine dose response, dose frequency and dose duration that provide maximum protection against HIV transmission.