Signature molecules expressed differentially in a liver disease stage-specific manner by HIV-1 and HCV co-infection

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dc.creatorWhitmill, Amanda
dc.creatorKim, Seongcheol
dc.creatorRojas, Vivian K.
dc.creatorGulraiz, Fahad
dc.creatorAfreen, Kazi
dc.creatorJain, Mamta
dc.creatorSingh, Meharvan
dc.creatorPark, In-Woo
dc.date.accessioned2022-11-15T22:34:38Z
dc.date.available2022-11-15T22:34:38Z
dc.date.issued2018-08-23
dc.description.abstractTo elucidate HIV-1 co-infection-induced acceleration of HCV liver disease and identify stage-specific molecular signatures, we applied a new high-resolution molecular screen, the Affymetrix GeneChip Human Transcriptome Array (HTA2.0), to HCV-mono- and HIV/HCV-co-infected liver specimens from subjects with early and advanced disease. Out of 67,528 well-annotated genes, we have analyzed the functional and statistical significance of 75 and 28 genes expressed differentially between early and advanced stages of HCV mono- and HIV/HCV co-infected patient liver samples, respectively. We also evaluated the expression of 25 and 17 genes between early stages of mono- and co-infected liver tissues and between advanced stages of mono- and co-infected patient's samples, respectively. Based on our analysis of fold-change in gene expression as a function of disease stage (i.e., early vs. advanced), coupled with consideration of the known relevant functions of these genes, we focused on four candidate genes, ACSL4, GNMT, IFI27, and miR122, which are expressed stage-specifically in HCV mono- and HIV-1/HCV co-infective liver disease and are known to play a pivotal role in regulating HCV-mediated hepatocellular carcinoma (HCC). Our qRT-PCR analysis of the four genes in patient liver specimens supported the microarray data. Protein products of each gene were detected in the endoplasmic reticulum (ER) where HCV replication takes place, and the genes' expression significantly altered replicability of HCV in the subgenomic replicon harboring regulatory genes of the JFH1 strain of HCV in Huh7.5.1. With respect to three well-known transferrable HIV-1 viral elements-Env, Nef, and Tat-Nef uniquely augmented replicon expression, while Tat, but not the others, substantially modulated expression of the candidate genes in hepatocytic cells. Combinatorial expression of these cellular and viral genes in the replicon cells further altered replicon expression. Taken together, these results showed that HIV-1 viral proteins can exacerbate liver pathology in the co-infected patients by disparate molecular mechanisms-directly or indirectly dysregulating HCV replication, even if lack of association of HCV load and end-stage liver disease in hemophilic patients were reported, and modulating expression of hepatocellular genes critical for disease progression. These findings also provide major insights into development of stage-specific hepatocellular biomarkers for improved diagnosis and prognosis of HCV-mediated liver disease.
dc.description.sponsorshipFunded by NIH/NIDDK R01 DK099055.
dc.identifier.citationWhitmill, A., Kim, S., Rojas, V., Gulraiz, F., Afreen, K., Jain, M., Singh, M., & Park, I. W. (2018). Signature molecules expressed differentially in a liver disease stage-specific manner by HIV-1 and HCV co-infection. PloS one, 13(8), e0202524. https://doi.org/10.1371/journal.pone.0202524
dc.identifier.issn1932-6203
dc.identifier.issue8
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31922
dc.identifier.volume13
dc.publisherPLOS
dc.relation.urihttps://doi.org/10.1371/journal.pone.0202524
dc.rights.holder© 2018 Whitmill et al.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePLoS One
dc.subject.meshCarcinoma, Hepatocellular / genetics
dc.subject.meshCarcinoma, Hepatocellular / pathology
dc.subject.meshCarcinoma, Hepatocellular / virology
dc.subject.meshCoinfection / genetics
dc.subject.meshCoinfection / pathology
dc.subject.meshCoinfection / virology
dc.subject.meshEndoplasmic Reticulum / genetics
dc.subject.meshEndoplasmic Reticulum / virology
dc.subject.meshGene Expression Regulation / genetics
dc.subject.meshHIV Infections / genetics
dc.subject.meshHIV Infections / pathology
dc.subject.meshHIV Infections / virology
dc.subject.meshHIV-1 / genetics
dc.subject.meshHIV-1 / pathogenicity
dc.subject.meshHepacivirus / genetics
dc.subject.meshHepacivirus / pathogenicity
dc.subject.meshHepatitis C / genetics
dc.subject.meshHepatitis C / pathology
dc.subject.meshHepatitis C / virology
dc.subject.meshHepatocytes / metabolism
dc.subject.meshHepatocytes / pathology
dc.subject.meshHumans
dc.subject.meshLiver Neoplasms / genetics
dc.subject.meshLiver Neoplasms / pathology
dc.subject.meshLiver Neoplasms / virology
dc.subject.meshTranscriptome / genetics
dc.subject.meshVirus Replication / genetics
dc.titleSignature molecules expressed differentially in a liver disease stage-specific manner by HIV-1 and HCV co-infection
dc.typeArticle
dc.type.materialtext

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