A SIV/Rhesus Monkey Penile Mucosal Transmission Model

描述(申请人提供)：男性生殖道是全球HIV-1感染的主要部位。因此，阻止阴茎粘膜中的HIV-1感染是遏制全球艾滋病流行不可或缺的一部分。预防HIV-1性传播的有效干预策略很可能需要在粘膜传播的最早阶段阻断病毒感染。开发有效的艾滋病疫苗/杀微生物剂的障碍之一是缺乏对建立粘膜艾滋病毒-1感染的早期发病机制的了解。尽管全世界1500万感染艾滋病毒的男性中的大多数是通过阴茎粘膜感染的，但人们对病毒进入男性生殖器隔间的确切途径知之甚少。此外，男性包皮环切术在防止异性恋男性感染HIV-1方面的保护作用背后的生物学基础仍不清楚。了解艾滋病毒-1在阴茎粘膜急性感染期间病毒进入和传播的初始事件，对于制定干预策略以阻断艾滋病毒-1在男性生殖道的粘膜传播至关重要。 我们的总体目标是阐明阴茎粘膜传播的免疫发病机制，这是艾滋病毒/艾滋病研究中一个重要但被忽视的领域。由于缺乏与生理相关的动物阴茎传播模型，理解与男性生殖道感染艾滋病毒-1有关的早期事件一直受到阻碍。到目前为止，还没有可靠的、特征良好的猴免疫缺陷病毒(SIV)/猕猴包皮感染模型发表。没有这种传播模式的原因是，从技术上讲，在非人类灵长类动物(NHP)中引发阴茎感染是非常困难的。为了克服这一障碍，我们利用了我们最近的理解，即TRIM5等位基因在调节印度源恒河猴的SIV粘膜获得方面发挥了作用。我们已经开发了一种将阴茎粘膜无损伤地暴露于SIV的技术，并证明了在包皮暴露后，恒河猴可获得系统性SIV感染，根据其TRIM5基因型别，恒河猴对粘膜感染相对更宽容。在R21的应用中，我们的目标是利用这种新的SIV/恒河猴阴茎感染模型来研究HIV-1在男性生殖道中的发病机制。为了实现这一点，我们将首先改进这种SIV阴茎传播模型，并确定它是否概括了粘膜HIV-1感染的关键病毒学和免疫学特征。然后，我们将使用这个系统来探索阴茎粘膜中HIV/SIV致病的早期事件。这些研究数据将证明SIV/恒河猴阴茎传播模型的有效性，阐明HIV-1在阴茎粘膜中的传播机制，并为剖析HIV-1在男性生殖器腔急性感染时的粘膜免疫发病机制奠定基础。这些见解将为开发合理的干预措施提供生物学基础，以防止艾滋病毒-1在男性中的性传播。 公共卫生相关性：尽管全世界大多数感染艾滋病毒的男性是通过阴茎粘膜感染的，但人们对病毒进入男性生殖道的确切途径知之甚少。我们将使用一种新的SIV/恒河猴阴茎感染模型来阐明HIV-1在男性生殖道的粘膜传播机制。这种动物粘膜传播模型有可能对制定干预策略以阻止人类男性生殖器粘膜感染HIV-1产生变革性影响。

DESCRIPTION (provided by applicant): The male genital tract constitutes a major site of HIV-1 infection worldwide. Therefore, blocking HIV-1 infection in the penile mucosa is integral to curbing the global AIDS epidemic. Effective intervention strategies to prevent the sexual transmission of HIV-1 most likely will need to interrupt viral infection during the earliest stages of mucosal transmission. One of the barriers to developing an effective AIDS vaccine/microbicide is a lack of understanding of the early pathogenesis in the establishment of mucosal HIV-1 infection. Although the majority of the 15 million HIV-infected men worldwide acquired infection via the penile mucosa, very little is known about the precise routes of viral entry into the male genital compartment. Furthermore, the biologic basis underlying the protective effect of male circumcision in preventing HIV-1 acquisition in heterosexual men remains unclear. Understanding the initial events of viral entry and dissemination during acute HIV-1 infection in the penile mucosa is critical for the design of intervention strategies to block HIV-1 mucosal transmission in the male genital tract. Our overall goal is to elucidate the immunopathogenesis of penile mucosal transmission, an important but neglected area of HIV/AIDS research. Understanding the early events associated with HIV-1 acquisition in the male genital tract has been hampered by the lack of a physiologically-relevant animal penile transmission model. To date, no reliable, well-characterized simian immunodeficiency virus (SIV)/rhesus monkey prepuce infection model has been published. The reason for the absence of this transmission model is that it has been technically very difficult to initiate penile infection in nonhuman primates (NHP). To overcome this hurdle, we exploited our recent understanding that TRIM5 alleles play a role in modulating mucosal acquisition of SIV in Indian-origin rhesus monkeys. We have developed a technique for atraumatically exposing the penile mucosa to SIV and demonstrated that systemic SIV infection can be achieved after prepuce exposures in rhesus monkeys that are relatively more permissive to mucosal infection on the basis of their TRIM5 genotypes. In this R21 application, our objective is to utilize this novel SIV/rhesus monkey penile infection model to study HIV-1 pathogenesis in the male genital tract. To accomplish this, we will first refine this SIV penile transmission model and determine whether it recapitulates key virologic and immunologic features of mucosal HIV-1 infection. We will then use this system to explore the early events of HIV/SIV pathogenesis in the penile mucosa. The data from these studies will demonstrate the validity of the SIV/rhesus monkey penile transmission model, illuminate the mechanisms of HIV-1 transmission in the penile mucosa, and form a foundation to dissect the mucosal immunopathogenesis of HIV-1 infection during acute infection in the male genital compartment. These insights will provide the biologic basis for developing rational interventions that prevent HIV-1 sexual transmission in men. PUBLIC HEALTH RELEVANCE: Although the majority of the HIV-infected men worldwide acquired infection via the penile mucosa, very little is known about the precise routes of viral entry into the male reproductive tract. We will use a novel SIV/rhesus monkey model of penile infection to elucidate the mechanisms of HIV-1 mucosal transmission in the male genital tract. This animal mucosal transmission model has the potential to have a transformative impact on developing intervention strategies to block HIV-1 acquisition in the human male genital mucosa.