試圖了解HIV感染過程的致病機制與防禦機制，並幫助臨床病毒感染的控制，研究宿主-病原體物種間交互作用是一個非常重要的研究課題。在這項研究中，經由宿主的高通量定序資料(次世代定序NGS)，病毒的RT-PCR資料以及後生miRNA資料及其他資訊，我們建構了宿主與病原體物種內與物種間蛋白質以及miRNA的交互作用(PPMI)網路在HIV的整個感染過程中。主要的PPMI網路被萃取出做為宿主 - 病原體串擾網絡在不同的HIV病毒感染階段。
經由分別比較不同HIV感染階段的宿主與病原體物種間串擾網路在HIV病毒感染細胞以及相對應的未感染的細胞中，宿主-病原體物種間串擾網路標記在各個HIV感染階段被萃取出。經由各個階段的宿主-病原體物種間串擾網路標記取交集，我們進一步找出共同的核心宿主 - 病原體串擾網絡標記在整個HIV感染階段。通過進一步調查這個共同的核心宿主 - 病原體串擾網絡標記的分子間交互作用以及病毒蛋白與宿主間交互作用的改變
我們可以得到更深入地了解艾滋病毒的發病機制和宿主的防禦機制。這可以提供新的藥物靶標設計方針並提高艾滋病的治療效率。

To investigate host-pathogen interspecies interactions is a very important research topic in attempts to understand pathogenic and defensive mechanisms in the HIV infection process and help control the clinic pathogenic infections. In this study, with the help of simultaneously two-sided time-course HIV-human high throughput sequencing data (next generation sequencing NGS), RT-PCR data, epigenetic miRNA data and other omic data, the interspecies protein-protein miRNA interaction (PPMI) network is constructed for host and pathogen interactions in the HIV infection process. Principal interspecies PPMI networks are extracted as host-pathogen crosstalk network at different stages of HIV infection process.
By comparing host-pathogen crosstalk networks in HIV infected cell with mock cell (without HIV infection) at different stages of HIV infection process respectively, host-pathogen crosstalk network markers at different infection stages are extracted. We further find the common core host-pathogen crosstalk network marker of the whole infection stage by the intersection of different stages host-pathogen crosstalk network markers. By further investigating this common core host-pathogen crosstalk network marker for molecular interaction shifting and viral proteins interaction in different HIV replication stages, we could get more insight into the pathologic mechanism of the HIV virus and the defense mechanism of human. This might offer the new way of drug target design for efficient therapies of AIDS.
Keywords: HIV; miRNA; AIDS; interspecies protein-protein miRNA interaction (PPMI) network; host-pathogen crosstalk network mark; pathological and defense mechanism

Content
ABTRACT i
INTRODUCTION 1
Chapter 2 7
Materials and Methods 7
2.1 Overview of construction framework for the interspecies PPMI network 7
2.2 Big Data mining and preprocessing 8
2.3 Selection of protein pool and construction of candidate interspecies protein-protein miRNA interaction (PPMI) network 9
2.4 Dynamic coupling model of host-pathogen interspecies PPMI network 10
2.5 Construction of PPMI network by system identification method and system order detection scheme 12
2.6 Determination of significant connection change proteins in PPMI network at different HIV infection stages via Differential score method 15
2.7 Find the common core host-pathogen crosstalk network marker 18
Chapter 3 23
Result 23
3.1 Functional analysis of core proteins in host-pathogen crosstalk network marker for each HIV replication stage 23
3.2Detailed analysis of common Core host-pathogen crosstalk network biomarker in different HIV infection stages 27
3.2-1 Core host-pathogen crosstalk network biomarker in the reverse transcription stage 28
3.2-2 Core host-pathogen crosstalk network biomarker in integration/replication stage 32
3.2-3 Core host-pathogen crosstalk network biomarker in the late stage 35
3.3 Specific host-pathogen crosstalk network biomarkers 40
3.3-1 Functional analysis of specific host-pathogen crosstalk network biomarker in the HIV reverses transcription stage 40
3.3-2 Functional analysis of specific host-pathogen crosstalk network biomarker in HIV integration/replication stage 42
3.3-3 Functional analysis of specific host-pathogen crosstalk network biomarker in the late stage of HIV infection process 44
3.4 Highlight the crosstalk between HIV virus and host 45
3.4-1 Functional analysis of crosstalks between host proteins and viral proteins in the integration/replication stage and late stages 45
3.4-2 The cellular roles of each viral protein at the HIV integration/replication stage 47
3.4-3 The cellular roles of each viral protein at the late stage 48
3.5 Identified multiple drug-targets 49
Chapter 4 51
Discussion 51
Chapter5 54
Conclusions 54
Supplementary 69

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