Chemokine Modulation During SIV Infection & AIDS

SIV 感染期间的趋化因子调节

• 批准号: 6947009
• 负责人: TODD A REINHART
• 金额: $ 38.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947009
• 关键词: HIV infections; Macaca; antiviral agents; chemokine; chemokine receptor; disease /disorder model; human immunodeficiency virus 1; immunopathology; immunotherapy; in situ hybridization; interferon gamma; lymphatic tissue; polymerase chain reaction; simian AIDSs; simian immunodeficiency virus; virus replication

DESCRIPTION (provided by applicant): HIV-1 infection and AIDS remain a major worldwide public health problem, and efforts toward understanding how the virus causes immunodeficiency and toward developing novel therapies are still required, despite the advent of highly active antiretroviral therapy (HAART). Increased homing of T cells to lymphoid tissues (LTs) during HIV-1 infection, with loss through direct infection/killing or bystander killing, has been proposed as one mechanism contributing to the development of immunodeficiency. In addition, increased homing of CD4+ T cells and its amelioration following HAART have been demonstrated in HIV-1- infected patients. The causes and consequences of altered homing of leukocytes to LTs are not fully understood and these issues constitute a major focus of this proposal. A comprehensive understanding of the mechanisms that lead to changes in homing to LTs will identify possible targets for immunotherapy. Our overall hypothesis for these studies is that alterations in chemokine expression in LTs contribute to the development of immunodeficiency during HIV-1 infection. Using the SIV/macaque model system, we have made initial observations regarding the alteration of chemokine expression in lymph nodes (LNs) and spleen, but comprehensive analyses are required to fully understand the magnitude of alterations and their causes and consequences. Based on our initial findings we have proposed a model for type 1, IFN-y-driven positive feedback loops that sustain the ongoing recruitment of type 1 T cells into LTs. However, this model has not been addressed experimentally and we propose to do exactly this by therapeutically modulating the recruitment of cells into LTs during SIV infection. The Specific Aims of this proposal are to: (1) Define alterations in the networks of chemokines in macaque LTs during pathogenic SIV infection; (2) Determine the biochemical properties of inflammatory and homeostatic macaque chemokines that could be involved in HIV/SIV immunopathogenesis; and (3) Determine the virologic and immunologic effects of systemic treatment of SIV infected macaques with chemokine receptor antagonists.

描述(申请人提供)：HIV-1感染和艾滋病仍然是一个主要的世界性公共卫生问题，尽管出现了高效抗逆转录病毒疗法(HAART)，但仍需努力了解该病毒如何导致免疫缺陷和开发新的治疗方法。在HIV-1感染过程中，T细胞向淋巴组织的归巢增加，通过直接感染/杀死或旁观者杀伤而丢失，已被认为是导致免疫缺陷发展的一种机制。此外，在HIV-1感染的患者中，已经证实了CD4+T细胞归巢增加以及HAART后的改善。改变白细胞归巢到LT的原因和后果尚不完全清楚，这些问题构成了本提案的主要焦点。全面了解导致归巢到LTS的变化的机制将确定免疫治疗的可能靶点。我们对这些研究的总体假设是，在HIV-1感染期间，LT中趋化因子表达的变化有助于免疫缺陷的发展。利用SIV/猕猴模型系统，我们已经初步观察了趋化因子在淋巴结(LNS)和脾中的表达变化，但需要进行全面的分析才能充分了解变化的程度及其原因和后果。基于我们的初步发现，我们为1型干扰素-γ驱动的正反馈环提出了一个模型，该模型支持1型T细胞向LT的持续招募。然而，这一模型还没有在实验上解决，我们建议通过治疗性地调节SIV感染期间细胞到LT中的招募来做到这一点。这一建议的具体目的是：(1)确定SIV感染过程中恒河猴LT中趋化因子网络的变化；(2)确定可能参与HIV/SIV免疫发病机制的炎性和动态平衡猕猴趋化因子的生化特性；(3)确定趋化因子受体拮抗剂全身治疗SIV感染猕猴的病毒学和免疫学效应。