MUCOSAL INFECTION OF MACAQUES WITH AN ACUTELY LETHAL SIV

致命性 SIV 对猕猴的粘膜感染

• 批准号: 2517301
• 负责人: Patricia N Fultz
• 金额: $ 36.47万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-15 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517301
• 关键词: Macaca nemestrina; T cell receptor; cytotoxic T lymphocyte; cytotoxicity; disease /disorder model; gut associated lymphoid tissue; immunocytochemistry; in situ hybridization; lymphocyte; macrophage; mucosa; mucosal immunity; simian immunodeficiency virus; virus diseases; virus replication

DESCRIPTION (based on applicant's abstract): The major route of transmission of HIV-1 is across mucosal surfaces between sexual partners or infected mothers and their fetuses or neonates. However, essentially nothing is known about the cells that facilitate passage of virus or virus-infected cells across mucosa or that are initially infected after passage of virus to primary sites of replication. To devise effective treatments and vaccines, it is important to understand the pathogenesis of HIV following mucosal transmission and to determine whether there are differences between mucosal and parenteral infection, in primary and secondary sites of virus replication, and in initial immune responses to the virus. Such insight into infectious diseases can be gained most efficiently through the use of animal models. Infection of pig- tailed macaques (Macaca nemestrina) with a virulent simian immunodeficiency virus, designated SIVsmmPBj14, provides several advantages over other SIV models. Two important advantages are: first, rapid onset of disease, which reproduces the multisystemic acute HIV-1 infection in humans and results in death in less than 2 weeks; and second, the virus preferentially replicates in gut-associated lymphoid tissue. Based on preliminary experiments indicating that the disease course following mucosal infection is altered relative to that observed after intravenous infection with SIVsmmPBj14, the following hypothesis will be tested: mucosal infection of pig-tailed macaques with SIVsmmPBj14 results in less severe disease sequelae than does intravenous infection because viral replication occurs in mucosal lymphocytes and macrophages. As a result, virus dissemination is inhibited more effectively by cytotoxic cells in mucosal tissues compared with similar effector cells induced in peripheral lymphoid organs after parenteral exposure. Macaques will be infected with SIVsmmPBj14 by atraumatic exposure of genital or rectal mucosal surfaces. At regular intervals during the first few hours and days after inoculation, animals will be euthanized and the kinetics of viral replication and dissemination, and tissue sites and cell types that support viral replication, will be determined using immunohistochemistry, in situ hybridization, and PCR-based assays. In addition, leukocytes that infiltrate areas of active SIV replication will be characterized phenotypically and functionally by assessing cell surface antigens, cytolytic activity, and use of specific T-cell receptor Vb and Vd gene segments. Finally, biologic and molecular properties of viruses isolated from peripheral and mucosal tissues and fluids will be determined. These studies should provide important insights into the earliest events that occur following mucosal infection by a primate lentivirus.

描述（基于申请人的摘要）： HIV-1通过性伴侣之间的粘膜表面传播 或受感染的母亲及其胎儿或新生儿。然而， 关于促进病毒通过的细胞或 病毒感染的细胞穿过粘膜或最初感染后， 病毒向主要复制位点的传播。制定有效 治疗和疫苗，重要的是要了解发病机制 艾滋病毒的粘膜传播后，并确定是否有 粘膜感染和肠外感染之间的差异，在原发性和 病毒复制的次要位点，以及初始免疫应答 对病毒的反应这种对传染病的洞察力， 有效地通过使用动物模型。猪尾感染 一种具有毒性猿免疫缺陷的猕猴 一种被命名为SIVsmmPBj 14的病毒与其它SIV相比具有几个优点 模型两个重要的优点是：第一，发病快， 其在人类中复制多系统急性HIV-1感染， 在不到两周内导致死亡;第二，病毒 优先在肠相关淋巴组织中复制。基于 初步实验表明， 粘膜感染相对于静脉注射后观察到的改变 感染SIVsmmPBj 14，将检验以下假设： 用SIVsmmPBj 14粘膜感染猪尾猕猴导致 比静脉内感染更轻的疾病后遗症，因为 病毒复制发生在粘膜淋巴细胞和巨噬细胞中。作为 结果，细胞毒性药物能更有效地抑制病毒传播， 与诱导的类似效应细胞相比， 在胃肠外暴露后的外周淋巴器官中。猕猴会 通过生殖器或直肠的非创伤性暴露感染SIVsmmPBj 14 粘膜表面。在最初的几个小时里， 在接种后30天，将动物安乐死，并观察其动力学。 病毒复制和传播，以及组织部位和细胞类型 支持病毒复制，将使用 免疫组织化学、原位杂交和基于PCR的测定。在 此外，浸润SIV复制活跃区域的白细胞 将通过评估细胞的表型和功能来表征 表面抗原、细胞溶解活性和特异性T细胞的应用 受体Vb和Vd基因片段。最后，生物和分子 从外周和粘膜组织分离的病毒的性质， 液体将被确定。这些研究将提供重要的 了解粘膜感染后发生的最早期事件 被灵长类慢病毒感染