PATHOBIO OF HIV(SIV)-INDUCED ANGIOPROLIFERATIVE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 原发性肺动脉高压(PPH)是一种进展迅速且通常是致命的疾病，其在HIV感染人群中的发病率比普通人群高出许多倍。遗憾的是，HIV相关性肺动脉高压(HRPH)的发病机制尚不清楚。然而，组织学上的相似之处是惊人的：内皮细胞(EC)不受控制的增殖和复合性病变的形成导致随后的右心衰竭使肺动脉管腔消失。免疫失调、肺部长期暴露于病毒产物以及趋化因子/细胞因子谱改变可能是造成损伤的原因之一。在肺部，HIV-1主要感染巨噬细胞，提供了潜在的病毒储存库和Nef等局部病毒蛋白的来源，Nef可以循环并影响周围细胞。由于缺乏合适的动物模型，HRPH的研究一直受到阻碍。由于许多灵长类动物的HIV-1模型概括了人类所见的免疫缺陷和并发症，我们对感染了含有HIV-1 Nef的SIV/HIV嵌合病毒(SHIVnefSF33A)的猕猴的肺进行了研究，发现Shiv-nef的肺中存在丛状病变，但在SIV Nef感染的猕猴中没有，这表明nef等位基因在促进肺血管重构的能力方面存在功能差异。我们建议研究感染SHIVnef的猴子的HRPH的自然历史和进展。我们的特定假设是，感染SHIVnef的猴子的免疫失调触发EC的表型转换，允许选择高度增殖、生长失调的EC群体，通过丛状病变形成来消除肺动脉管腔。为了研究这一问题，我们将解决以下问题：在感染SHIVnef的猕猴中，在伽马疱疹病毒感染的背景下，PH的自然历史是什么？我们将感染猴子，跟踪感染后PH的发展，并将免疫学参数与病变形成相关联。HIV nef是否导致肺微血管内皮细胞获得增殖性表型？我们将检测肺内皮细胞暴露于各种nef等位基因/突变或暴露于巨噬细胞的条件培养液后的体外增殖特性。使用在系统发育上与人类非常接近的灵长类动物模型系统，使我们能够研究HRPH的启动和发展阶段。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary pulmonary hypertension (PPH), a rapidly progressive and usually fatal disease, has an incidence rate among the HIV infected population many times higher than in the general population. Unfortunately, the pathogenesis of HIV-related pulmonary hypertension (HRPH) is not well understood. Nevertheless, the histological similarities are striking: uncontrolled endothelial cell (EC) proliferation and formation of plexogenic lesions obliterate the Lumina of the pulmonary arteries with subsequent right heart failure. The immune dysregulation, chronic exposure to viral products in the lung and altered chemokine/cytokine profile may contribute to the injury. In the lung, HIV-1 infects primarily macrophages providing a potential reservoir of virus and a source of localized viral proteins such as Nef, which can circulate and affect surrounding cells. Studies of HRPH have been hampered by lack of a suitable animal model. Since numerous primate models of HIV-1 recapitulate the immune deficiencies and complications seen in humans, we undertook a study of lungs from macaques infected with an SIV/HIV chimeric virus containing HIV-1 Nef (SHIVnefSF33A) and found plexogenic lesions in the lungs of SHIV-nef but not in SIV Nef-infected macaques, suggesting that there are functional differences between the nef alleles in their ability to promote pulmonary vascular remodeling. We propose to study the natural history and progression of HRPH in SHIVnef infected monkeys. Our specific hypothesis is that immune dysregulation of SHIVnef-infected monkeys, triggers a phenotypic switch in EC that allows selection of a highly proliferative, growth-dysregulated EC population that obliterates the Lumina of pulmonary arteries through plexiform lesion formation. To study this, we will address the following question: What is the natural history of PH in macaques infected with SHIVnef, and in a background of gammaherpesvirus infection? We will infect the monkeys, track PH development post-infection, and will correlate immunological parameters with lesion formation. Does HIV nef lead to the acquisition of a proliferative phenotype in lung microvascular EC? We will examine the in vitro proliferative properties of pulmonary endothelial cells after exposure to various nef alleles/mutants or to conditioned media from macrophages exposed to these as well. Using a primate model system that is phylogenetically very close to humans allows us to study both the initiation and progression phases of HRPH.