title: Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection identified by transcriptome profiling of PBMCs.
abstract: BACKGROUND
  Despite the easy accessibility and diagnostic utility of PBMCs and their potential to show distinct expression patterns associated with the accelerated disease progression in HIV/HCV co-infection, there has not been a systematic study focusing on the global dysregulations of the biological pathways in PBMCs from HIV, HCV mono- and co-infected individuals. This study aimed at identifying the transcriptome distinctions of PBMCs between these patient groups.
  
  
  METHODS
  Genome-wide transcriptomes of PBMCs from 10 HIV/HCV co-infected patients, 7 HIV+ patients, 5 HCV+ patients, and 5 HIV/HCV sero-negative healthy controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA) to detect the global dysregulations of the biological pathways between HIV, HCV mono- and co-infection.
  
  
  RESULTS
  Forty-one, 262, and 44 DEGs with fold change > 1.5 and FDR (false discovery rate) <0.05 for the comparisons of HCV versus co-infection, HIV versus co-infection, and HIV versus HCV were identified, respectively. Significantly altered pathways (FDR < 0.05), featured by those involved in immune system, signaling transduction, and cell cycle, were detected. Notably, the differential regulation of cytotoxicity pathway discriminated between HIV, HCV mono- and co-infection (up-regulated in the former versus the latter group: co-infection versus HIV or HCV, HIV versus HCV; FDR <0.001 ~ 0.019). Conversely, the cytokine-cytokine receptor interaction pathway was down-regulated in co-infection versus either HCV (FDR = 0.003) or HIV (FDR = 0.028). For the comparison of HIV versus HCV, the cell cycle (FDR = 0.016) and WNT signaling (FDR = 0.006) pathways were up- and down-regulated in HIV, respectively.
  
  
  CONCLUSIONS
  Our study is the first to identify the differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection, which may reflect the distinct patterns of virus-host cell interactions underlying disease progression. Further inspection of cytotoxicity pathway has pinned down to the expression of the KIR genes to be associated with specific patterns of particular virus-host interactions. Between HIV and HCV, the altered cell cycle and WNT signaling pathways may suggest the different impact of HIV and HCV on cell proliferation and differentiation.
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, Newcastle, NSW, 2308, Australia. jingqin.wu@newcastle.edu.au.
authors.forename: Jing Qin
authors.initials: JQ
authors.lastname: Wu
authors.affiliation: Herpes Virus Pathogenesis Lab, Center for Virus Research, Westmead Millennium Institute, University of Sydney, Westmead, Sydney, NSW, 2145, Australia. monica.saksena@sydney.edu.au.
authors.forename: Monica Miranda
authors.initials: MM
authors.lastname: Saksena
authors.affiliation: Department of Infectious Diseases, Hospital Carlos III, Sinesio Delgado 10, 28029, Madrid, Spain. vsoriano@dragonet.es.
authors.forename: Vincent
authors.initials: V
authors.lastname: Soriano
authors.affiliation: Department of Infectious Diseases, Hospital Carlos III, Sinesio Delgado 10, 28029, Madrid, Spain. mvispo@gmail.com.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Vispo
authors.affiliation: Retroviral Genetics Division, Center for Virus Research, Westmead Millennium Institute & Westmead Hospital, University of Sydney, Westmead, Sydney, NSW, 2145, Australia. nitin.saksena@sydney.edu.au.
authors.forename: Nitin K
authors.initials: NK
authors.lastname: Saksena
mesh_terms: D002470:Cell Survival; D060085:Coinfection / Q000473:pathology* / Q000821:virology; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000150:complications / Q000473:pathology*; D006505:Hepatitis / Q000150:complications / Q000473:pathology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000821:virology*; D046228:Microarray Analysis