Abstract
To 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.
Highlights
Due to the shared routes of infection, HIV-1/HCV co-infection is common, with 15–30% of all HIV-1-infected persons estimated to be co-infected [1, 2]
It is known that the shed Env glycoprotein or gp120 associated with HIV-1 virions can directly interact with CXCR4 or CCR5 expressed on the surface of hepatocytes and transduce signals to alter HCV viral and HCV-infected cellular gene expression of hepatocytes [14, 15, 24]
Values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in all but KV5 and KV7 and KV11 patients fell within normal ranges, and viremia was detected in the periphery of a few co-infected patients (KK8, KV11, and KV12), where the number of CD4 cells in KV11 and KV12 was below 350/ml, even under the combination anti-retroviral therapy (cART) treatment
Summary
Due to the shared routes of infection, HIV-1/HCV co-infection is common, with 15–30% of all HIV-1-infected persons estimated to be co-infected [1, 2]. HIV-1 Tat secreted from HIV-1 infected cells can diffuse into hepatocytes and augment HCV replication and certain hepatocellular genes to accelerate liver disease, as reported previously [25, 26]. HIV-1 Nef can be transferred from HIV1-infected cells to the neighboring cells through conduits (filopodia) and/or exosomes [23, 27,28,29,30], and the transferred protein in the target hepatocytes can dysregulate hepatocellular biology. It is unknown at present how HIV-1 and/or viral proteins induce these alterations in aggravating disease
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