Bioresponsive Combination Microbicide Delivery System for HIV and HSV

描述(申请人提供)：全世界有4200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，以减缓或阻止艾滋病毒在男性和女性之间的性传播，这种药物被称为杀微生物剂。此外，艾滋病毒的性传播往往得益于其他因素的存在。来自30多项流行病学研究的数据表明，感染单纯疱疹病毒2型(HSV-2)与感染艾滋病毒-1的风险增加约两到四倍有关。由于单纯疱疹病毒2型在普通人群中的流行，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组合杀菌剂，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。我们将在模拟单纯疱疹病毒感染者HIV传播的希夫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，有两个互补但独立的目标，我们将同时努力实现。第一个目标是设计和制备一种具有生物响应性的复合杀菌剂，它由一种自组装凝胶组成，这种凝胶在阴道pH值时是半固体，在精液pH时液化。凝胶中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(邻苯二甲酸纤维素)。这些凝胶将在体外和体内进行释放率、抗病毒活性和毒性测试。根据这一数据，将确定两种铅配方。第二个目标是开发和验证猿类艾滋病毒(在灵长类动物模型中模拟人类艾滋病毒感染的SHV感染)。为了解决抗HIV杀微生物剂在HSV感染高发人群中的有效性，我们将在病毒联合感染灵长类动物模型中测试联合杀菌剂。我们将首先在猕猴身上建立和验证产生病毒脱落和疾病发展的SHV和HSV剂量。在R33阶段，这个灵长类动物模型将用于评估最有希望的杀微生物剂配方的有效性和安全性，该配方包含病毒中和剂(CAP)和抗病毒药物(TNFV和ACV)，可提供最大限度的保护，防止艾滋病毒传播。计划在3-5年进行的此类实验将确定提供最大保护以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.