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. 2021 Mar 30;28(1):23.
doi: 10.1186/s12929-021-00718-6.

HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients

Óscar Brochado  1 , Isidoro Martínez  2 , Juan Berenguer  3   4 , Luz Medrano  1 , Juan González-García  5   6 , María Ángeles Jiménez-Sousa  1 , Ana Carrero  3   4 , Víctor Hontañón  5   6 , Jordi Navarro  7   8 , Josep M Guardiola  9 , Amanda Fernández-Rodríguez #  1 , Salvador Resino #  10 ; GESIDA Study Group
Collaborators, Affiliations

HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients

Óscar Brochado et al. J Biomed Sci. .

Abstract

Objective: To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients.

Methods: We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE).

Results: HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2, PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1, and the most downregulated were IFI44 and IFI44L. These 58 SDE genes revealed two significantly enriched pathways (FDR < 0.05), one linked to Epstein-Barr virus infection and another related to p53 signaling. For HIV/HCV-f vs. HIV-mono group, we found 44 SDE genes that revealed 31 enriched pathways (FDR < 0.05) related to inflammation, cancer/cell cycle alteration, viral and bacterial infection, and comorbidities associated with HIV/HCV-coinfection. Five genes were overrepresented in most pathways (JUN, NFKBIA, PIK3R2, CDC42, and STAT3).

Conclusion: HIV/HCV-coinfected patients who eradicated hepatitis C with IFN-based therapy showed profound gene expression changes after achieving sustained virological response. The altered pathways were related to inflammation and liver-related complications, such as non-alcoholic fatty liver disease and hepatocellular carcinoma, underscoring the need for active surveillance for these patients.

Keywords: Gene expression; HCV clearance; HIV/HCV coinfection; Immune system; Interferon therapy; PBMCs.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the study design. A total of 27,173 genes were identified by RNA sequencing. Of these, 4723 genes from the immune system were selected from InnateDB, and 3935 genes were selected for differential expression analysis. The FilterByExpr function was applied for each comparison: a HIV/HCV-b vs. HIV-mono, 521 genes were selected, six were SDE genes not involved in any biological pathway; b HIV/HCV-f vs. HIV/HCV-b, 1124 genes were selected, 58 were SDE genes involved in two biological pathways; c HIV/HCV-f vs. HIV-mono, 504 genes were selected, 44 were SDE genes involved in 31 biological pathways. HIV, human immunodeficiency virus; HCV, hepatitis C virus; HIV/HCV-b, HIV/HCV-coinfected patients at baseline; HIV/HCV-f, HIV/HCV-coinfected patients 24 weeks after SVR; HIV-mono, HIV-monoinfected patients; SDE, significantly differentially expressed
Fig. 2
Fig. 2
Volcano plots for differentially expressed genes between groups: a HIV/HCV-b versus HIV-mono, b HIV/HCV-f versus HIV/HCV-b, c HIV/HCV-f versus HIV-mono. Volcano-plot discriminates by FDR and log2(FC). The red vertical lines represent the cut-off of FC 1.5 and the blue horizontal line indicates the cut-off of FDR = 0.05. Green dots represent genes significantly altered with FDR ≤ 0.05 and absolute FC ≥ 1.5. FDR, false discovery rate for multiple comparisons using Benjamini and Hochberg procedure; FC, fold-change; HIV, human immunodeficiency virus; HCV, hepatitis C virus; HIV/HCV-b, HIV/HCV-coinfected patients at baseline; HIV/HCV-f, HIV/HCV-coinfected patients 24 weeks after SVR; HIV-mono, HIV-monoinfected patients
Fig. 3
Fig. 3
The chord-diagram represents connections between SDE genes (left-side) and pathways (right-side) in comparing HIV/HCV-f versus HIV-mono. Red corresponds to inflammation, green corresponds to cell cycle alteration and cancer, blue corresponds to viral and bacterial infection, and black corresponds to complications related to HIV/HCV-coinfection. HIV, human immunodeficiency virus; HCV, hepatitis C virus; HIV/HCV-b, HIV/HCV-coinfected patients at baseline; HIV/HCV-f, HIV/HCV-coinfected patients 24 weeks after SVR; HIV-mono, HIV-monoinfected patients; SDE, significantly differentially expressed
Fig. 4
Fig. 4
Venn diagram of the SDE genes in the three comparisons analyzed in the study: a HIV/HCV-b versus HIV-mono, b HIV/HCV-f versus HIV/HCV-b, c HIV/HCV-f versus HIV-mono. The number in each circle corresponds to the number of SDE genes in the different comparisons. The overlapping numbers are the number of SDE genes shared between the different comparisons. The non-overlapping numbers are the unique SDE genes in each comparison. HIV, human immunodeficiency virus; HCV, hepatitis C virus; HIV/HCV-b, HIV/HCV-coinfected patients at baseline; HIV/HCV-f, HIV/HCV-coinfected patients 24 weeks after SVR; HIV-mono, HIV-monoinfected patients
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