Pathogenesis of SIV in African green monkeys

描述(由申请者提供)：本项目的目标是研究SIVagm在非洲绿猴(AGM)中的发病机制。该物种能够应对SIVagm的高水平复制，而不会产生负面后果。我们对股东周年大会如何做到这一点的理解是有限的。我们的初步结果描述了SIVagm感染在AGM中的悖论，其特征是：a)高血浆VLS，相当于病理性SIV感染；b)缺乏“经典”SIV靶细胞(定义为CD4+CCR5+CD45RAneg T细胞)；c)在慢性SIVagm感染中保存CD4+T细胞。因此，我们推测在致病性和非致病性SIV感染之间在靶细胞、免疫细胞表型、组织病毒复制部位和体内病毒动力学方面存在数量上的差异，这可能解释了这种自然宿主对艾滋病的耐药性。为了验证这一假设，我们提出了以下特定的目标(SA)：SA1：将SIVagm在加勒比起源的AGM中的致病机制与由SIVagm引起的易感染AIDS的异源宿主；猪尾猕猴(PTM)的致病机制进行比较。这两个物种感染SIVagm的临床结果不同，但研究仅限于血浆中的VLS。感染SIVagm的AGM和PTM的免疫学数据很少。因此，我们的建议将集中在SIVagm感染的AGM和PTMS组织中的病毒和免疫学参数。我们将对感染同一SIVagm株的这两个宿主的病毒复制部位、细胞表型、增殖和凋亡进行比较。此外，SIVagm的主要目标细胞将在两个主机上确定。SA2：检测SIVagm病毒在体内的动态，并确定SIVagm感染的AGM和PTM中短寿命和长寿命细胞对血浆总病毒载量的相对贡献。SIVagm感染在其自然宿主中的悖论表明，致病模型和非致病模型在病毒爆发大小、病毒清除率或各种靶细胞的寿命方面存在潜在差异。我们将使用类似于SIVmac和HIV-1的方法，比较SIVagm在AGM和PTM中的体内动力学和靶细胞。 这些目标加在一起，旨在确定对艾滋病产生抵抗力的病毒和/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.