A SIV/Rhesus Monkey Penile Mucosal Transmission Model

SIV/恒河猴阴茎粘膜传播模型

• 批准号: 8210220
• 负责人: SAMPA SANTRA
• 金额: $ 22.19万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210220
• 关键词: AIDS Vaccines; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Alleles; Animals; Area; Cells; Data; Epidemic; Event; Foundations; Genotype; Goals; HIV; HIV-1; Heterosexuals; Immunologics; Infection; Intervention; Macaca mulatta; Male Circumcision; Male Genital Organs; Modeling; Mucous Membrane; Pathogenesis; Play; Publishing; Research; Role; Route; SIV; Sexual Transmission; Site; Staging; System; Techniques; Viral; Virus; Virus Diseases; base; design; effective intervention; human male; insight; male; men; microbicide; neglect; nonhuman primate; novel; prepuce; prevent; protective effect; reproductive; transmission process; virus pathogenesis

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.

描述（由申请人提供）：男性生殖道是全球HIV-1感染的主要部位。因此，阻断阴茎粘膜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早期阶段中断病毒感染。开发有效的艾滋病疫苗/杀微生物剂的障碍之一是缺乏对粘膜HIV-1感染的早期发病机制的了解。尽管全世界1500万艾滋病毒感染者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的确切途径知之甚少。此外，男性包皮环切术预防异性恋男性感染HIV-1的生物学基础尚不清楚。了解HIV-1急性阴茎粘膜感染期间病毒进入和传播的初始事件对于设计阻断HIV-1在男性生殖道粘膜传播的干预策略至关重要。