Modulation of HIV-1 infection by CCL18

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。病毒复制解释了病毒发病机制的许多方面，通常反映了刺激和抑制宿主因子之间的平衡，其中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表征病毒与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。趋化因子家族的一些成员具有潜在的抗HIV-1活性，而其他成员则刺激HIV-1感染。我们的数据显示，TH2趋化因子CCL18在HIV-1感染患者中显著增加，并选择性地增强了X4病毒在亚优化激活T细胞中的复制，很可能是通过激活细胞内信号通路。我们的数据进一步表明，在巨噬细胞中，HIV-1感染增加了CCL18的表达，这可以通过TH2细胞因子和CCL18的自我扩增能力进一步上调。本提案的目标是确定CCL18增强X4病毒复制的机制，并确定CCL18增强生产所涉及的途径。具体目标将验证HIV-1感染直接或间接（通过调节细胞因子水平）触发巨噬细胞中CCL18表达增加的假设，这反过来通过激活细胞内信号通路选择性地增加T细胞中HIV-1 X4株的复制，从而增强病毒复制。利用原代淋巴细胞和巨噬细胞，在目的1中，我们将定义由CCL18在T细胞中增强的病毒生命周期中的步骤，并确定由CCL18激活的参与增强病毒复制的定义步骤的信号通路。在目的2中，我们将确定在hiv -1感染、IL-4、IL-10和CCL18处理的巨噬细胞中参与CCL18表达增加的细胞内通路。使用联合方法，我们将定义触发CCL18表达增加的共同途径及其潜在的相互作用。总之，拟议的研究有望产生新的发现，确定CCL18与病毒之间相互作用的机制。

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.