Li Cheng-Wei, Chen Bor-Sen
Laboratory of Control and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
Curr HIV Res. 2018;16(1):77-95. doi: 10.2174/1570162X16666180219155324.
Two big issues in the study of pathogens are determining how pathogens infect hosts and how the host defends itself against infection. Therefore, investigating host-pathogen interactions is important for understanding pathogenicity and host defensive mechanisms and treating infections.
In this study, we used omics data, including time-course data from high-throughput sequencing, real-time polymerase chain reaction, and human microRNA (miRNA) and protein-protein interaction to construct an interspecies protein-protein and miRNA interaction (PPMI) network of human CD4+ T cells during HIV-1 infection through system modeling and identification.
By applying a functional annotation tool to the identified PPMI network at each stage of HIV infection, we found that repressions of three miRNAs, miR-140-5p, miR-320a, and miR-941, are involved in the development of autoimmune disorders, tumor proliferation, and the pathogenesis of T cells at the reverse transcription stage. Repressions of miR-331-3p and miR-320a are involved in HIV-1 replication, replicative spread, anti-apoptosis, cell proliferation, and dysregulation of cell cycle control at the integration/replication stage. Repression of miR-341-5p is involved in carcinogenesis at the late stage of HIV-1 infection.
By investigating the common core proteins and changes in specific proteins in the PPMI network between the stages of HIV-1 infection, we obtained pathogenic insights into the functional core modules and identified potential drug combinations for treating patients with HIV-1 infection, including thalidomide, oxaprozin, and metformin, at the reverse transcription stage; quercetin, nifedipine, and fenbendazole, at the integration/replication stage; and staurosporine, quercetin, prednisolone, and flufenamic acid, at the late stage.
病原体研究中的两个重大问题是确定病原体如何感染宿主以及宿主如何抵御感染。因此，研究宿主 - 病原体相互作用对于理解致病性、宿主防御机制以及治疗感染至关重要。
在本研究中，我们使用组学数据，包括来自高通量测序、实时聚合酶链反应的时间进程数据以及人类微小RNA（miRNA）和蛋白质 - 蛋白质相互作用数据，通过系统建模和识别构建HIV - 1感染期间人类CD4 + T细胞的种间蛋白质 - 蛋白质和miRNA相互作用（PPMI）网络。
通过将功能注释工具应用于HIV感染各阶段识别出的PPMI网络，我们发现三种miRNA，即miR - 140 - 5p、miR - 320a和miR - 941的抑制作用与自身免疫性疾病的发展、肿瘤增殖以及逆转录阶段T细胞的发病机制有关。miR - 331 - 3p和miR - 320a的抑制作用与整合/复制阶段的HIV - 1复制、复制性传播、抗凋亡、细胞增殖以及细胞周期控制失调有关。miR - 341 - 5p的抑制作用与HIV - 1感染后期的致癌作用有关。
通过研究HIV - 1感染阶段之间PPMI网络中的共同核心蛋白和特定蛋白的变化，我们获得了对功能核心模块的致病见解，并确定了用于治疗HIV - 1感染患者的潜在药物组合，包括逆转录阶段的沙利度胺、奥沙普秦和二甲双胍；整合/复制阶段的槲皮素、硝苯地平和芬苯达唑；以及后期的星形孢菌素、槲皮素、泼尼松龙和氟芬那酸。
