HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients
Authors: Brochado Óscar , Martínez Isidoro , Berenguer Juan , Medrano Luz , González-García Juan , Jiménez-Sousa María Ángeles , Carrero Ana , Hontañón Víctor , Navarro Jordi , Guardiola Josep M. , Fernández-Rodríguez Amanda , Resino Salvador ,   the GESIDA Study Group, Carrero A. , Miralles P. , López J. C. , Parras F. , Padilla B. , Aldamiz-Echevarría T. , Tejerina F. , Díez C. , Pérez-Latorre L. , Fanciulli C. , Gutiérrez I. , Ramírez M. , Carretero S. , Bellón J. M. , Bermejo J. , Berenguer J. , Hontañón V. , Arribas J. R. , Montes M. L. , Bernardino I. , Pascual J. F. , Zamora F. , Peña J. M. , Arnalich F. , Díaz M. , González-García J. , Domingo P. , Guardiola J. M. , Van den Eynde E. , Pérez M. , Ribera E. , Crespo M. , Casado J. L. , Dronda F. , Moreno A. , Pérez-Elías M. J. , Sanfrutos M. A. , Moreno S. , Quereda C. , Arranz A. , Casas E. , de Miguel J. , Schroeder S. , Sanz J. , Sanz J. , Santos I. , Bustinduy M. J. , Iribarren J. A. , Rodríguez-Arrondo F. , Von-Wichmann M. A. , Vergas J. , Téllez M. J. , Vinuesa D. , Muñoz L. , Hernández-Quero J. , Ferrer A. , Galindo M. J. , Ortiz L. , Ortega E. , Montero M. , Blanes M. , Cuellar S. , Lacruz J. , Salavert M. , López-Aldeguer J. , Pérez G. , Gaspar G. , Yllescas M. , Crespo P. , Aznar E. , Esteban H. 
Published: March 2021

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.