Investigating HIV-Human Interaction Networks to Unravel Pathogenic Mechanism for Drug Discovery: A Systems Biology Approach

Curr HIV Res. 2018;16(1):77-95. doi: 10.2174/1570162X16666180219155324.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: AIDS; HIV; Host-pathogen interaction network; Interspecies protein-protein miRNA interaction network; Multiple drug; miRNA..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Computational Biology
  • Data Mining
  • Drug Discovery / methods
  • Gene Expression Profiling
  • Gene Expression Regulation
  • HIV Infections / genetics
  • HIV Infections / immunology
  • HIV Infections / metabolism
  • HIV Infections / virology*
  • HIV-1 / drug effects
  • HIV-1 / physiology*
  • Host-Pathogen Interactions* / genetics
  • Host-Pathogen Interactions* / immunology
  • Humans
  • Models, Theoretical
  • Protein Interaction Mapping
  • Protein Interaction Maps
  • Systems Biology / methods

Substances

  • Anti-HIV Agents