Dataset Information

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

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.

SUBMITTER: Brochado O

PROVIDER: S-EPMC8010945 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Systemic inflammation, endothelial dysfunction and coagulopathy are of high clinical relevance in the management of people living with HIV (PLWH), and even more in patients coinfected with hepatitis C virus (HCV). It has been suggested a significant impact of HCV coinfection on these conditions. However, HCV can be eradicated in most patients with the new direct-acting antivirals (DAAs) therapy. We have analyzed the effect of HCV on systemic inflammation, endothelial activation and coagulopathy in PLWH and its evolution after HCV eradication with DAAs. Twenty-five HIV/HCV coinfected (HIV/HCV group), 25 HIV monoinfected (HIV group) and 20 healthy controls (HC) were included in the study. All patients were on ART and HIV suppressed. Levels of fourteen markers of systemic inflammation, endothelial activation and coagulopathy (IL-1ß, IL-6, IL-12p70, IL-8, TNFα, D-dimer, Eotaxin, IL-18, IP-10, monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), TNFα receptor 1 (TNFR1), vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1)) were measured on plasma at baseline and after DAAs-mediated HCV eradication. Non-parametric tests were used to establish inter/intra-group differences. At baseline, the HIV/HCV group showed increased levels of IL-18 (p = 0.028), IP-10 (p < 0.0001), VCAM-1 (p < 0.0001) and ICAM-1 (p = 0.045), compared to the HC and HIV groups, with the highest levels for IL18 and IP10 observed in HIV/HCV patients with increased liver stiffness (≥7.1 KPa). Eradication of HCV with DAAs-based therapy restored some but not all the evaluated parameters. VCAM-1 remained significantly increased compared to HC (p = 0.001), regardless of the level of basal liver stiffness in the HIV/HCV group, and IP-10 remained significantly increased only in the HIV/HCV group, with increased level of basal liver stiffness compared to the HC and to the HIV groups (p = 0.006 and p = 0.049, respectively). These data indicate that DAAs therapy in HIV/HCV co-infected patients and HCV eradication does not always lead to the normalization of systemic inflammation and endothelial dysfunction conditions, especially in cases with increased liver stiffness.