MUCOSAL INFECTION OF MACAQUES WITH AN ACUTELY LETHAL SIV

描述(基于申请人的摘要)：主要路线 HIV-1通过性伴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，从本质上讲， 对促进病毒传播的细胞一无所知 跨粘膜的病毒感染细胞或最初感染后 病毒传播到复制的主要地点。想出有效的办法 治疗和疫苗，了解发病机制是很重要的 在粘膜传播后感染艾滋病毒，并确定是否存在 粘膜感染与肠外感染的区别 病毒复制和初始免疫反应的次要部位 对病毒来说。对传染病的这种洞察力是最能获得的 通过使用动物模型来有效地进行。猪尾巴感染 具有致命性猴免疫缺陷的猕猴(Macaca Nomestrina) 病毒，命名为SIVsmmPBj14，与其他SIV相比有几个优点 模特们。两个重要的优点是：第一，疾病起病快， 在人类体内复制了多系统的急性HIV-1感染 导致不到两周的死亡；第二，病毒 优先在肠道相关淋巴组织中复制。基于 初步实验表明，该病的病程 与静脉注射后观察到的粘膜感染相比，粘膜感染发生了改变 感染SIVsmmPBj14，将检验以下假设： SIVsmmPBj14感染猪尾猕猴的黏膜感染 疾病后遗症没有静脉感染那么严重，因为 病毒复制发生在粘膜淋巴细胞和巨噬细胞中。作为一名 结果，细胞毒更有效地抑制了病毒的传播 粘膜组织中的细胞与同类效应细胞的比较 在非肠道暴露后的外周淋巴器官中。猕猴会 因生殖器或直肠无创暴露而感染SIVsmmPBj14 粘膜表面。在最初的几个小时内以固定的时间间隔 接种后几天，动物将被安乐死，其动力学 病毒复制和传播以及组织部位和细胞类型 支持病毒复制的，将使用 免疫组织化学、原位杂交和聚合酶链式反应检测。在……里面 此外，渗入活跃的SIV复制区域的白细胞 将通过评估细胞来表征表型和功能 表面抗原、细胞溶解活性和特定T细胞的使用 受体Vb和Vd基因片段。最后，生物和分子 从外周和粘膜组织中分离的病毒的特性和 体液将被确定。这些研究应该提供重要的 对粘膜感染后发生的最早事件的洞察 被灵长类慢病毒感染。

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.