Interferon-related gene array in predicting the efficacy of interferon therapy in chronic hepatitis B_Journal of Biomedical Engineering

Authors：

WANG Jiayi ^1,2 , LU Jiajie ^1,2 , ZHOU Chen ³ , DU Lingyao ^1,2 ,  TANG Hong ^1,2

1. Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;
2. Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;
3. West China School of Medicine, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

TANG Hong, Email: htang6198@hotmail.com

Keywords：

Chronic hepatitis B; Interferons; Gene array; Treatment response

DOI：

10.7507/1001-5515.202301014

Video：

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This study aims to clarify host factors of IFN treatment in the treatment of chronic hepatitis B (CHB) patients by screening the differentially expressed genes of IFN pathway CHB patients with different response to interferon (IFN) therapy. Three cases were randomly selected in IFN-responding CHB patients (Rs), non-responding CHB patients (NRs) and healthy participants, respectively. The human type I IFN response RT² profiler PCR array was used to detect the expression levels of IFN-related genes in peripheral blood monocytes (PBMCs) from healthy participants and CHB patients before and after Peg-IFN-α 2a treatment. The results showed that more differentially expressed genes appeared in Rs group than NRs group after IFN treatment. Comparing with healthy participants, IFNG, IL7R, IRF1, and IRF8 were downregulated in both Rs and NRs group before IFN treatment; CXCL10, IFIT1, and IFITM1 were upregulated in the Rs; IL13RA1 and IFI35 were upregulated in the NRs, while IFRD2, IL11RA, IL4R, IRF3, IRF4, PYHIN1, and ADAR were downregulated. The expression of IL15, IFI35 and IFI44 was downregulated by 4.09 (t = 10.58, P < 0.001), 5.59 (t = 3.37, P = 0.028) and 10.83 (t = 2.8, P = 0.049) fold in the Rs group compared with the NRs group, respectively. In conclusion, IFN-response-related gene array is able to evaluate IFN treatment response by detecting IFN-related genes levels in PBMC. High expression of CXCL10, IFIT1 and IFITM1 before treatment may suggest satisfied IFN efficacy, while high expression of IL13RA1, IL15, IFI35 and IFI44 molecules and low expression of IFRD2, IL11RA, IL4R, IRF3, IRF4, PYHIN1 and ADAR molecules may be associated with poor IFN efficacy.

Citation： WANG Jiayi, LU Jiajie, ZHOU Chen, DU Lingyao, TANG Hong. Interferon-related gene array in predicting the efficacy of interferon therapy in chronic hepatitis B. Journal of Biomedical Engineering, 2023, 40(1): 79-86. doi: 10.7507/1001-5515.202301014 Copy

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2.	Wu Y-L, Shen C-L, Chen X-Y. Antiviral treatment for chronic hepatitis B: Safety, effectiveness, and prognosis. World J Clin Cases, 2019, 7(14): 1784-1794.
3.	Tan M, Bhadoria A S, Cui F, et al. Estimating the proportion of people with chronic hepatitis B virus infection eligible for hepatitis B antiviral treatment worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol, 2021, 6(2): 106-119.
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6.	Ning Q, Han M, Sun Y, et al. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol, 2014, 61(4): 777-784.
7.	Hu Peng, Shang Jia, Zhang Wenhong, et al. HBsAg loss with Peg-interferon alfa-2a in hepatitis B patients with partial response to nucleos(t)ide analog: New switch study. J Clin Transl Hepatol, 2018, 6(1): 25-34.
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13.	Antonczyk A, Krist B, Sajek M, et al. Direct inhibition of IRF-dependent transcriptional regulatory mechanisms associated with disease. Front Immunol, 2019, 10: 1176.
14.	Massa D, Baran M, Bengoechea J A, et al. PYHIN1 regulates pro-inflammatory cytokine induction rather than innate immune DNA sensing in airway epithelial cells. J Biol Chem, 2020, 295(14): 4438-4450.
15.	Pestal K, Funk C C, Snyder J M, et al. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity, 2015, 43(5): 933-944.
16.	Li T, Yang X, Li W, et al. ADAR1 stimulation by IFN-α downregulates the expression of MAVS via RNA editing to regulate the anti-HBV response. Mol Ther, 2021, 29(3): 1335-1348.
17.	Sonneveld M J, Arends P, Boonstra A, et al. Serum levels of interferon-gamma-inducible protein 10 and response to peginterferon therapy in HBeAg-positive chronic hepatitis B. J Hepatol, 2013, 58(5): 898-903.
18.	Sixtos-Alonso M S, Sánchez-Muñoz F, Sánchez-Ávila J F, et al. IFN-stimulated gene expression is a useful potential molecular marker of response to antiviral treatment with Peg-IFNα 2b and ribavirin in patients with hepatitis C virus genotype 1. Arch Med Res, 2011, 42(1): 28-33.
19.	Xie D-Y, Wang S-M, Yang J-M, et al. IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection. World J Gastroenterol, 2016, 22(44): 9813-9821.
20.	Wilkins C, Woodward J, Lau D T-Y, et al. IFITM1 is a tight junction protein that inhibits hepatitis C virus entry. Hepatology, 2013, 57(2): 461-469.
21.	Das A, Dinh P X, Panda D, et al. Interferon-inducible protein IFI35 negatively regulates RIG-I antiviral signaling and supports vesicular stomatitis virus replication. J Virol, 2014, 88(6): 3103-3113.
22.	Busse D C, Habgood-Coote D, Clare S, et al. Interferon-induced protein 44 and interferon-induced protein 44-like restrict replication of respiratory syncytial virus. J Virol, 2020, 94(18): e00297-20.
23.	Hallen LC, Burki Y, Ebeling M, et al. Antiproliferative activity of the human IFN-α-inducible protein IFI44. J Interferon Cytokine Res, 2007, 27(8): 675-680.

1. World Health Organization. Hepatitis B. (2022-06-24) [2023-01-06]. https: //www.who.int/news-room/factsheets/detail/hepatitis-b.
2. Wu Y-L, Shen C-L, Chen X-Y. Antiviral treatment for chronic hepatitis B: Safety, effectiveness, and prognosis. World J Clin Cases, 2019, 7(14): 1784-1794.
3. Tan M, Bhadoria A S, Cui F, et al. Estimating the proportion of people with chronic hepatitis B virus infection eligible for hepatitis B antiviral treatment worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol, 2021, 6(2): 106-119.
4. Yeh M-L, Huang J-F, Dai C-Y, et al. Pharmacokinetics and pharmacodynamics of pegylated interferon for the treatment of hepatitis B. Expert Opin Drug Metab Toxicol, 2019, 15(10): 779-785.
5. He Y, Zhou Y, Wang H, et al. The efficacy of pegylated interferon alpha-2a and entecavir in HBeAg-positive children and adolescents with chronic hepatitis B. BMC Pediatr, 2022, 22(1): 426.
6. Ning Q, Han M, Sun Y, et al. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol, 2014, 61(4): 777-784.
7. Hu Peng, Shang Jia, Zhang Wenhong, et al. HBsAg loss with Peg-interferon alfa-2a in hepatitis B patients with partial response to nucleos(t)ide analog: New switch study. J Clin Transl Hepatol, 2018, 6(1): 25-34.
8. Han Q, Zhang C, Zhang J, et al. The role of innate immunity in HBV infection. Semin Immunopathol, 2013, 35(1): 23-38.
9. Chiale C, Marchese A M, Robek M D. Innate immunity and HBV persistence. Curr Opin Virol, 2021, 49: 13-20.
10. Wang J, Du L, Tang H. Suppression of interferon-α treatment response by host negative factors in hepatitis B virus infection. Front Med, 2021, 8: 784172.
11. 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版). 中华传染病杂志, 2019, 37(12): 711-736.
12. McNab F, Mayer-Barber K, Sher A, et al. Type I interferons in infectious disease. Nat Rev Immunol, 2015, 15(2): 87-103.
13. Antonczyk A, Krist B, Sajek M, et al. Direct inhibition of IRF-dependent transcriptional regulatory mechanisms associated with disease. Front Immunol, 2019, 10: 1176.
14. Massa D, Baran M, Bengoechea J A, et al. PYHIN1 regulates pro-inflammatory cytokine induction rather than innate immune DNA sensing in airway epithelial cells. J Biol Chem, 2020, 295(14): 4438-4450.
15. Pestal K, Funk C C, Snyder J M, et al. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity, 2015, 43(5): 933-944.
16. Li T, Yang X, Li W, et al. ADAR1 stimulation by IFN-α downregulates the expression of MAVS via RNA editing to regulate the anti-HBV response. Mol Ther, 2021, 29(3): 1335-1348.
17. Sonneveld M J, Arends P, Boonstra A, et al. Serum levels of interferon-gamma-inducible protein 10 and response to peginterferon therapy in HBeAg-positive chronic hepatitis B. J Hepatol, 2013, 58(5): 898-903.
18. Sixtos-Alonso M S, Sánchez-Muñoz F, Sánchez-Ávila J F, et al. IFN-stimulated gene expression is a useful potential molecular marker of response to antiviral treatment with Peg-IFNα 2b and ribavirin in patients with hepatitis C virus genotype 1. Arch Med Res, 2011, 42(1): 28-33.
19. Xie D-Y, Wang S-M, Yang J-M, et al. IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection. World J Gastroenterol, 2016, 22(44): 9813-9821.
20. Wilkins C, Woodward J, Lau D T-Y, et al. IFITM1 is a tight junction protein that inhibits hepatitis C virus entry. Hepatology, 2013, 57(2): 461-469.
21. Das A, Dinh P X, Panda D, et al. Interferon-inducible protein IFI35 negatively regulates RIG-I antiviral signaling and supports vesicular stomatitis virus replication. J Virol, 2014, 88(6): 3103-3113.
22. Busse D C, Habgood-Coote D, Clare S, et al. Interferon-induced protein 44 and interferon-induced protein 44-like restrict replication of respiratory syncytial virus. J Virol, 2020, 94(18): e00297-20.
23. Hallen LC, Burki Y, Ebeling M, et al. Antiproliferative activity of the human IFN-α-inducible protein IFI44. J Interferon Cytokine Res, 2007, 27(8): 675-680.

Journal of Biomedical Engineering

Interferon-related gene array in predicting the efficacy of interferon therapy in chronic hepatitis B

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