Modulation of HIV-1 infection by CCL18

描述(申请人提供)：HIV-1感染的发病机制反映了病毒和宿主之间的动态相互作用。病毒复制是病毒致病机制的多个方面，通常反映了刺激和抑制宿主因素之间的平衡，包括内源性细胞因子和趋化因子。HIV-1感染本身可能会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，以及这种相互作用的网络对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艾滋病毒-1活性，而其他成员则刺激艾滋病毒-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X4病毒在次优激活的T细胞中的复制，最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，TH2细胞因子和CCL18的自我扩增能力可以进一步上调CCL18的表达。这项建议的目标是确定CCL18增强X4病毒复制的机制，并确定参与增强CCL18生产的途径。这些特定的目标将检验这一假设，即HIV-1感染(通过调节细胞因子水平)直接或间接地触发巨噬细胞CCL18的表达增加，进而通过激活促进病毒复制的细胞内信号通路选择性地增加HIV-1X4毒株在T细胞中的复制。利用原代淋巴细胞和巨噬细胞，在目标1中，我们将确定CCL18在T细胞中增强病毒生命周期的步骤(S)，并确定参与促进病毒复制的已定义步骤(S)的信号通路。在目标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表达增加的细胞内途径。使用组合方法，我们将定义共同的途径及其潜在的相互作用，触发CCL18的表达增加。总之，拟议的研究有望产生新的发现，定义CCL18和病毒之间相互作用所涉及的机制。 公共卫生相关性：在HIV-1感染患者中检测到的CCL18水平升高可能通过支持在HIV-1感染期间出现更多致病性X4病毒而在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这一观察的潜在基础上，并有望提供新的发现，定义HIV-1感染增加CCL18表达的机制以及CCL18反过来选择性地促进HIV-1X4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，两项研究的结果都有望产生新的知识，可用于针对HIV-1感染期间X4病毒的扩展的新方法。

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.