Modulation of HIV-1 infection by CCL18

CCL18 对 HIV-1 感染的调节

• 批准号: 7569998
• 负责人: Helena Schmidtmayerova
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569998
• 关键词: Accounting; Address; CCL18 gene; CCL2 gene; CCL3 gene; CCL4 gene; Cells; Data; Dose; Environment; Equilibrium; Family; Foundations; Future; Goals; HIV-1; In Vitro; Infection; Integration Host Factors; Interleukin-10; Interleukin-4; Knowledge; Life Cycle Stages; Lymphocyte; MAP Kinase Gene; MAPK14 gene; Outcome; Pathogenesis; Pathway interactions; Patients; Plasma; Play; Population; Production; RANTES; Research; Research Technics; Role; STAT3 gene; STAT6 gene; Signal Pathway; Small Interfering RNA; System; T-Lymphocyte; Testing; Viral; Viral Load result; Viral Pathogenesis; Virus; Western Blotting; Work; base; chemokine; cytokine; in vivo; latent infection; macrophage; member; novel; novel strategies; public health relevance

DESCRIPTION (provided by applicant): The pathogenesis of HIV-1 infection reflects the dynamic interaction between the virus and the host. Viral replication that accounts for many aspects of viral pathogenesis generally mirrors a balance between stimulatory and inhibitory host factors, which include endogenous cytokines and chemokines. HIV-1 infection itself may further modulate this balance. The long-term goal of this project is to characterize the interactions between the virus and endogenous chemokines and the impact of this interactive network on HIV-1 pathogenesis. Several members of the chemokine family possess a potential anti-HIV-1 activity, while others stimulate HIV-1 infection. Our data show that the TH2 chemokine, CCL18 is significantly increased in HIV-1- infected patients and selectively enhances replication of X4 viruses in sub-optimally activated T cells, most likely via activation of intracellular signaling pathways. Our data further suggest that in macrophages, HIV-1 infection increases expression of CCL18, which can be further upregulated by TH2 cytokines and by self- amplification capability of CCL18. The goal of this proposal is to define the mechanisms by which CCL18 enhances replication of X4 viruses and determine pathways involved in enhanced production of CCL18. The specific aims will test the hypothesis that HIV-1 infection directly and indirectly (by modulating cytokine levels) triggers increased expression of CCL18 in macrophages, which in turn selectively increases replication of HIV-1 X4 strains in T cells via activation of intracellular signaling pathways that enhance viral replication. Using primary lymphocytes and macrophages, in aim 1 we will define step(s) in viral life cycle enhanced by CCL18 in T cells and determine signaling pathways activated by CCL18 involved in the enhancement of the defined step(s) of viral replication. In aim 2, we will determine intracellular pathways involved in increased expression of CCL18 in HIV-1-infected, IL-4, IL-10, and CCL18-treated macrophages. Using combined approaches, we will define common pathways and their potential interactions triggering increased expression of CCL18. Together, the proposed studies are expected to generate novel findings defining the mechanisms involved in the interplay between CCL18 and the virus. PUBLIC HEALTH RELEVANCE: Increased levels of CCL18 detected in HIV-1-infected patients may play a role in HIV-1 pathogenesis by supporting emergence of more pathogenic X4 viruses during HIV-1 infection. Therefore, studies proposed in this application focus on underlying basis of this observation and are expected to provide novel findings defining the mechanisms by which HIV-1 infection increases expression of CCL18 and the mechanisms by which CCL18 in turn selectively enhances replication of HIV-1 X4 viruses. We anticipate that proposed studies will provide a strong foundation for future in vivo studies and the results from both are expected to generate a new knowledge exploitable in novel approaches targeting expansion of X4 viruses during HIV-1 infection.

描述（由申请人提供）：HIV-1感染的发病机制反映了病毒与宿主之间的动态相互作用。解释病毒发病机制的许多方面的病毒复制通常反映刺激性和抑制性宿主因子之间的平衡，所述宿主因子包括内源性细胞因子和趋化因子。HIV-1感染本身可能进一步调节这种平衡。该项目的长期目标是描述病毒和内源性趋化因子之间的相互作用以及这种相互作用网络对HIV-1发病机制的影响。趋化因子家族的几个成员具有潜在的抗HIV-1活性，而其他成员则刺激HIV-1感染。我们的数据显示，TH 2趋化因子CCL 18在HIV-1感染患者中显著增加，并选择性地增强X4病毒在次最佳活化T细胞中的复制，最有可能是通过激活细胞内信号传导途径。我们的数据进一步表明，在巨噬细胞中，HIV-1感染增加了CCL 18的表达，这可以通过TH 2细胞因子和CCL 18的自我扩增能力进一步上调。本提案的目标是确定CCL 18增强X4病毒复制的机制，并确定CCL 18增强产生的途径。具体目标将测试以下假设：HIV-1感染直接和间接（通过调节细胞因子水平）触发巨噬细胞中CCL 18表达增加，从而通过激活增强病毒复制的细胞内信号传导途径选择性增加HIV-1 X4毒株在T细胞中的复制。使用原代淋巴细胞和巨噬细胞，在目标1中，我们将定义T细胞中由CCL 18增强的病毒生命周期中的步骤，并确定由CCL 18激活的参与增强病毒复制的定义步骤的信号传导途径。在目标2中，我们将确定在HIV-1感染、IL-4、IL-10和CCL 18处理的巨噬细胞中CCL 18表达增加所涉及的细胞内途径。使用组合的方法，我们将确定共同的途径和它们的潜在相互作用触发CCL 18的表达增加。总之，拟议的研究预计将产生新的发现，定义CCL 18和病毒之间相互作用的机制。 公共卫生相关性：在HIV-1感染患者中检测到的CCL 18水平升高可能通过支持HIV-1感染期间致病性更强的X4病毒的出现而在HIV-1发病机制中发挥作用。因此，本申请中提出的研究集中在该观察的潜在基础上，并预期提供新的发现，其定义了HIV-1感染增加CCL 18表达的机制和CCL 18进而选择性增强HIV-1 X4病毒复制的机制。我们预计，拟议的研究将为未来的体内研究提供坚实的基础，预计两者的结果将产生新的知识，可用于HIV-1感染期间X4病毒扩增的新方法。