Pathogenesis of SIV in African green monkeys

描述（由申请人提供）：本项目的目的是研究非洲绿色猴（AGM）中SIVagm的发病机制。该物种能够科普高水平的SIVagm复制而不会产生负面影响。我们对年度股东大会如何能够做到这一点的理解是有限的。我们的初步结果描述了AGM中SIVagm感染的矛盾，其特征在于：a）高血浆VL，相当于致病性SIV感染; B）缺乏“经典”SIV靶细胞（定义为CD 4 + CCR 5 + CD 45 RA阴性T细胞; c）在慢性SIVagm感染中保留CD 4 + T细胞。因此，我们推测，有定量的差异，在靶细胞，免疫细胞表型，组织病毒复制的网站和体内病毒动力学之间的致病性和非致病性SIV感染，这可能解释艾滋病在这个自然宿主的抗性。为了检验这一假设，我们提出了以下具体目标（SA）：SA 1：比较SIVagm在加勒比海起源的AGM中的发病机制与对SIVagm引起的AIDS易感的异源宿主的发病机制;猪尾猕猴（PTM）。这两个种属报告了SIVagm感染的不同临床结局，但研究仅限于血浆中的VL。很少有关于SIVagm感染的AGM和PTM的免疫学数据。因此，我们的建议将集中在SIVagm感染的AGM和PTM组织中的病毒和免疫学参数。我们将比较这两个主机感染相同的SIVagm株的病毒复制，细胞表型，增殖和凋亡的网站。此外，将在两种宿主中确定SIVagm的主要靶细胞。SA2：研究体内SIVagm病毒动力学，并确定SIVagm感染的AGM和PTM中短寿命和长寿命细胞对总血浆病毒载量的相对贡献。SIVagm在其天然宿主中感染的悖论表明致病性和非致病性模型在病毒爆发大小、病毒清除率或各种类型靶细胞的寿命方面存在潜在差异。我们将使用已用于SIVmac和HIV-1的类似方法，比较AGM和PTM中SIVagm的体内动力学和靶细胞。 结合起来，这些目标旨在确定负责抵抗艾滋病的病毒和/或宿主因素。

DESCRIPTION (provided by applicant): The objective of this project is to examine the pathogenesis of SIVagm in African green monkeys (AGMs). This species is able to cope with high levels of SIVagm replication without negative consequences. Our understanding of how AGMs are able to do this is limited. Our preliminary results depict a paradox of SIVagm infection in AGMs, characterized by: a) high plasma VLs, equivalent to pathogenic SIV infections; b) a paucity of "classical" SIV target cells (defined as CD4+CCR5+CD45RAneg T cells and; c) preservation of CD4+ T cells in chronic SIVagm infection. Therefore, we hypothesize that there are quantitative differences in target cells, immune cell phenotypes, sites of tissue viral replication and in vivo viral dynamics between pathogenic and non-pathogenic SIV infections which may explain the resistance to AIDS in this natural host. To examine this hypothesis, we propose the following Specific Aims (SA): SA1: To compare the pathogenesis of SIVagm in AGMs of Carribean origin to that of a heterologous host susceptible to AIDS caused by SIVagm; pig-tailed macaques (PTMs). A different clinical outcome of SIVagm infection was reported for these two species, but studies were limited to VLs in plasma. Few immunologic data is available for SIVagm-infected AGMs and PTMs. Therefore, our proposal will focus on viral and immunological parameters in tissues of SIVagm-infected AGMs and PTMs. We will compare these two hosts infected with the same SIVagm strain for sites of viral replication, cell phenotypes, proliferation and apoptosis. Also, the major target cells for SIVagm will be determined in both hosts. SA2: To examine SIVagm viral dynamics in vivo, and to determine the relative contribution of short and long-lived cells to the total plasma viral loads in SIVagm-infected AGMs and PTMs. The paradox of SIVagm infection in its natural host suggests potential differences between pathogenic and non-pathogenic models in viral burst size, viral clearance rates or the life span of various types of target cells. We will compare the in vivo dynamics and target cells of SIVagm in AGMs and PTMs, using similar approaches that have been used for SIVmac and HIV-1. Combined, these aims are designed to determine the viral and/or host factors responsible for resistance to AIDS.