Chemokine Modulation During SIV Infection & AIDS

SIV 感染期间的趋化因子调节

• 批准号: 7018528
• 负责人: TODD A REINHART
• 金额: $ 38.65万
• 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/7018528
• 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（由申请人提供）：HIV-1感染和艾滋病仍然是一个主要的全球公共卫生问题，尽管出现了高效抗逆转录病毒疗法（HAART），但仍需要努力了解病毒如何导致免疫缺陷并开发新的治疗方法。在HIV-1感染期间，T细胞向淋巴组织（lt）的归巢增加，通过直接感染/杀死或旁观者杀死而丢失，已被认为是促进免疫缺陷发展的一种机制。此外，在HIV-1感染患者中，CD4+ T细胞的归巢增加及其在HAART治疗后的改善已被证实。白细胞向lt的归巢改变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LTs归巢改变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，LTs中趋化因子表达的改变有助于HIV-1感染期间免疫缺陷的发展。利用SIV/猕猴模型系统，我们对淋巴结和脾脏趋化因子表达的改变进行了初步观察，但需要全面分析以充分了解改变的幅度及其原因和后果。基于我们的初步发现，我们提出了一个1型的模型，ifn -y驱动的正反馈循环维持了1型T细胞进入lt的持续招募。然而，这个模型还没有得到实验的解决，我们建议通过治疗性地调节SIV感染期间细胞向LTs的募集来做到这一点。本提案的具体目的是：(1)确定致病性SIV感染期间猕猴LTs趋化因子网络的变化；(2)确定可能参与HIV/SIV免疫发病的炎性和稳态猕猴趋化因子的生化特性；(3)确定趋化因子受体拮抗剂对SIV感染猕猴的全身治疗的病毒学和免疫学效果。