Bioresponsive Combination Microbicide Delivery System for HIV and HSV

描述（由申请人提供）：全世界有超过4200万HIV感染者，HIV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，世界许多地区的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，以减缓或阻止艾滋病毒的男性对女性的性传播与称为杀微生物剂的代理。此外，艾滋病毒的性传播往往由于其他因素的存在而得到帮助。来自30多项流行病学研究的数据表明，单纯疱疹病毒2型（HSV-2）感染与艾滋病毒1感染风险增加约2至4倍有关。由于HSV-2在一般人群中的流行，我们认识到这是艾滋病毒传播的一个重要恶化因素。该项目的总体目标是开发和优化一种多功能复合杀微生物剂，即使在HSV-2高流行率的人群中也能安全有效地预防艾滋病毒传播。我们将在模拟HSV感染者中HIV传播的SHIV恒河猴模型中评价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，有两个互补但独立的目标，我们将同时努力。第一个目标是设计和配制由自组装凝胶组成的生物响应性组合杀微生物剂，所述自组装凝胶在阴道pH下为半固体，在精液pH下为凝胶。所述凝胶将装载有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（邻苯二甲酸乙酸纤维素）。将在体外和体内测试凝胶的释放速率、抗病毒活性和毒性。根据这些数据，将确定两种铅制剂。第二个目标是开发和验证猿类HIV（在灵长类动物模型中模拟人类HIV感染的SHIV感染）。为了解决抗艾滋病毒杀微生物剂在单纯疱疹病毒感染高发人群中的有效性，我们将在病毒合并感染灵长类动物模型中测试组合杀微生物剂。我们将首先在猕猴中建立和验证SHIV和HSV剂量，以产生病毒脱落和疾病发展。在R33阶段，该灵长类动物模型将用于评估含有病毒中和剂（CAP）和抗病毒剂（TNFV和ACV）的最有前途的杀微生物剂制剂在提供最大保护以防止HIV传播方面的功效和安全性。计划在第3-5年进行的这类实验将确定提供最大保护防止艾滋病毒传播的剂量反应、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.