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УДК: 612.017:619 DOI:10.33920/MED-12-2107-07

Интерфероны и интерферонотерапия. Обзор литературы

Гизингер О.А. д-р биол. наук, профессор, ФГАОУ ВО «Российский университет дружбы народов», Медицинский институт, кафедра микробиологии и вирусологии, г. Москва, ул. Миклухо-Маклая, 8 919 319 4604, е-mail: ogizinger@gmail.com, ORCID 0000-0001-9302-0155

В статье описаны типы и биологические особенности интерферонов, которые являются составной частью противовирусной защиты организма. Показаны возможности применения интерферонов, индукторов интерферонов в комплексной терапии острых респираторных вирусных инфекций. Проанализирована обоснованность применения препаратов интерферонов для лечения и профилактики острых респираторных вирусных инфекций с учетом сведений о механизмах их действия и клинико-иммунологической эффективности.

Литература:

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2. Stetson D. B. Medzhitov R. Type I interferons in host defense. Immunity. 2006; 25: 373–381

3. Lavoie T. B., Kalie E., Crisafulli-Cabatu S., Abramovich R., Di Gioia G., Moolchan K., Pestka S., Schreiber G. 2011. Binding and activity of all human alpha interferon subtypes. Cytokine 56:282–289. doi: 10.1016/j.cyto.2011.07.019

4. Stark, G. R.; Darnell, J. E., Jr. The JAK-STAT pathway at twenty. Immunity 2012, 36, 503–514

5. HaibinYu, Hongwei Zhang, Ying Liu, Yanxiang Huang, LinaMa, Lai We, Hao Wu Reversible inhibition of murine cytomegalovirus replication by gamma interferon (IFN-γ) in primary macrophages involves a primed type I IFN-signaling subnetwork for full establishment of an immediate-early antiviral state. J. Virol. 2011; 85: 10286–10299

6. Odorizzi, P. M.; Wherry, E.J. Immunology an interferon paradox. Science 2013, 340, 155–1556.

7. Zhou H., Chen S., Wang M., Cheng A. Interferons and their receptors in birds: a comparison of gene structure, phylogenetic analysis, and cross modulation. Int J Mol Sci. 2014 Nov 14;15 (11):21045–68. doi: 10.3390/ijms151121045

8. Teijaro J. R. Pleiotropic roles of type 1 interferons in antiviral immune responses //Advances in immunology. — Academic Press, 2016. — Т. 132. — С. 135–158.

9. Gresser I. On intuition and the discovery of interferon. Cytokine Growth Factor Rev. 2015 Apr;26 (2):99–101. doi: 10.1016/j.cytogfr.2014.11.006. Epub 2014 Nov 22. PubMed PMID: 25547990.

10. Matsuyama N. The dinucleotide microsatellite polymorphism of IFNAR1 gene promoter correlates with responsiveness of hepatitis C patients to interferon. Hepatol. Res. 2003; 25: 221–22510

11. ShanRen, HaibinYu, Hongwei Zhang, Ying Liu, Yanxiang Huang, Lina Ma,. HaoWu. Polymorphisms of interferon-inducible genes OAS associated with interferon-α treatment response in chronic HBV infection. Antiviral Res. 2011; 89: 232–237

12. Persico M. Elevated expression and polymorphisms of SOCS3 influence patient response to antiviral therapy in chronic hepatitis C. Gut. 2008; 57: 507–515

13. Y. Arimori, R. Nakamura, H. Yamada, K. Shibata, N. Maeda, T. Kase. Type I interferon limits influenza virus-induced acute lung injury by regulation of excessive inflammation in mice Antiviral Research, 99 (2013), pp. 230–237

14. Hayden F. G., Fritz R., Lobo M. C., Alvord W., W. Strober S. E., Straus Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense The Journal of clinical investigation, 101 (1998), pp. 643–649

15. Davidson S. Crotta, T. M. McCabe, A. WackPathogenic potential of interferon alphabeta in acute influenza infection Nature Communications, 5 (2014), p. 3864].

16. R. Channappanavar A. R. Fehr, R. Vijay, M. Mack, J. Zhao, D. K. Meyerholz.Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice Cell Host & Microbe, 19 (2016), pp. 181–193

17. Narayanan K. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells J. Virol. 2008; 82: 4471–4479

18. Kamitani W. A two-pronged strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein.Nat. Struct. Mol. Biol. 2009; 16: 1134–1140

19. Ying Li, Chao Li., Peng Xue., Bo Zhong, Ai-Ping Mao, Yong Ran, He Chen, Yan-Yi Wang, Fuquan Yang, and Hong-Bing ShuISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. 05.2009. 106 (19): 7945–50. doI: 10.1073 / pnas.0900818106

20. Ahn J., Xia T., Rabasa A. Capote D. Betancourt G. N. Barber Extrinsic phagocyte-dependent STING signaling dictates the immunogenicity of dying cells Cancer Cell, 33 (2018) 862–873.e5

21. H. Ma, W. Yang, L. Zhang, S. Liu, M. Zhao, G. Zhou, L. Wang, S. Jin, Z. Zhang, J. HuInterferonalpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma Br.J. Cancer, 120 (2019), pp. 317–330

22. Ospelnikova T. P, Noseikina E. M., Gaiderova L. A., Ershov F. I. Therapeutic potential of alphainterferon preparations dur- ing socially significant human diseases of viral etiology. Zh Mikrobiol Epidemiol Immunobiol. 2016 Sep; (5):109–121. Review.Russian

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30. Berry C. M. Understanding Interferon Subtype Therapy for Viral Infections: Harnessing the Power of the Innate Immune System. Cytokine Growth Factor Rev. 2016 Oct; 31:83–90. doi: 10.1016/j.cytogfr.2016.08.001

31. European Medicines Agency. Committee for medicinal products for human use. Guidelines on the clinical investigation of the pharmacokinetics of therapeutic proteins. 2005.

32. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/ WC500003031.pdf.Accessed 15.03.2020].

33. Poreaux C, Bronowicki J-P, Debouverie M, et al. Managing generalized interferon-induced eruptions and the effectiveness of desensitization. Clin Exp Allergy. 2014; 44:756–764], имеет незначительные побочные эффекты за счет низкой иммуногенности

34. Baldo B. A. Side effects of cytokines approved for therapy. Drug Saf. 2014 Nov;37 (11):921–43. doi: 10.1007/s40264-014-0226-z

35. Negro F. Adverse effects of drugs in the treatment of viral hepatitis. Best Pract Res Clin Gastroenterol. 2010; 24:183–92.

36. Kraus M. R., Schäfer A., Faller HPsychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry. 2003; 64:708–714

37. Negro F. Adverse effects of drugs in the treatment of viral hepatitis. Best Pract Res Clin Gastroenterol. 2010; 24:183–192

38. FDA. CDER Therapeutic Biologic Products. CDER billable biologic product list. http://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/default.htm. Accessed 15.03.2020

39. Constant A., Castera L., Dantzer R., Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005;66: 1050–1057

40. Schaefer M., Horn M., Schmidt F., Correlation betweensICAM-1 and depressive symptoms during adjuvant treatment of melanoma with interferon alpha. Brain Behav Immun. 2004;18:555–562.

41. Raison C. L., Demetrashvili M, Capuron L. Neuropsychiatric adverse effects of interferonalpha: recognition and management. CNS Drugs. 2005; 19:105–123

42. Bocci V. Pharmacology and side-effects of interferons. Antiviral Res. 1994 Jul;24 (2-3):111– 119.

43. Вахитов Х. М., Пикуза О. И., Вахитова Л. Ф., Закирова А. М., Ризванова Ф. Ф. Индукторы интерферона в профилактике и лечении респираторных инфекций у детей // Российский вестник перинатологии и педиатрии. — 2019. — № 64 (3). — С. 103–108. https://doi.org/1 0.21508/1027-4065-2019-64-3-103-108

44. Tothova E. Immune-mediated complications during interferon alpha therapy in chronic myelogenous leukemia //Neoplasma. 2002. Т. 49. №. 2. С. 91–94

45. Abbott I. J, Chang C. C., Skinner MJ. Development and management of systemic lupus erythematosus in an HIV-infected man with hepatitis C and B co-infection following interferon therapy: a case report. J. Med Case Rep. 2009; 3:7289

46. Yagyu H., Okada K, Sato S., Pegylated interferon-alpha2b and ribavirin combination therapy induces Hashitoxicosis followed by type 1 diabetes mellitus. Diabetes Res Clin Pract. 2012;95: e52–4.1

47. Pinto JL, Pinto ME. Tiroiditis autoinmune inducida por interferón en pacientes con infección por virus de la hepatitis C [Interferon-induced autoimmune thyroiditis in a patient with hepatitis C virus infection.] Diferencias clínicas y polisomnográficas entre obesos y no obesos con síndrome de apneas-hipopneas del sueño Rey de Castro, Jorge; Rosales-Mayor, Edmundo Rev Peru Med Exp Salud Publica. 2011; 28:382–4.127

48. Agarwal SK, Lal C, Zaidi SH. Lupus activation with cerebritis following pegylated interferon in a hemodialysis patient. Nat. Rev. Nephrol. 2009; 5:599–603

49. Buie J.J. IFN-α negatively regulates the expression of endothelial nitric oxide synthase and nitric oxide production: implications for systemic lupus erythematosus //The Journal of Immunology. — 2017. — Т. 199. — №. 6. — С. 1979–1988

50. Rebecca L. Casazza, Helen M. Lazear,Jonathan J. Miner Protective and Pathogenic Effects of Interferon Signaling During Pregnancy Published Online: 13 Jan 2020 https://doi. org/10.1089/vim.2019.0076

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1. Zhou H., Chen S., Wang M., Cheng A. Interferons and their receptors in birds: a comparison of gene structure, phylogenetic analysis, and cross modulation. Int J Mol Sci. 2014 Nov 14;15 (11):21045–68. doi: 10.3390/ijms151121045

2. Stetson D. B. Medzhitov R. Type I interferons in host defense. Immunity. 2006; 25: 373–381

3. Lavoie T. B., Kalie E., Crisafulli-Cabatu S., Abramovich R., Di Gioia G., Moolchan K., Pestka S., Schreiber G. 2011. Binding and activity of all human alpha interferon subtypes. Cytokine 56:282–289. doi: 10.1016/j.cyto.2011.07.019

4. Stark, G. R.; Darnell, J. E., Jr. The JAK-STAT pathway at twenty. Immunity 2012, 36, 503–514

5. HaibinYu, Hongwei Zhang, Ying Liu, Yanxiang Huang, LinaMa, Lai We, Hao Wu Reversible inhibition of murine cytomegalovirus replication by gamma interferon (IFN-γ) in primary macrophages involves a primed type I IFN-signaling subnetwork for full establishment of an immediate-early antiviral state. J. Virol. 2011; 85: 10286–10299

6. Odorizzi, P. M.; Wherry, E.J. Immunology an interferon paradox. Science 2013, 340, 155–1556.

7. Zhou H., Chen S., Wang M., Cheng A. Interferons and their receptors in birds: a comparison of gene structure, phylogenetic analysis, and cross modulation. Int J Mol Sci. 2014 Nov 14;15 (11):21045–68. doi: 10.3390/ijms151121045

8. Teijaro J. R. Pleiotropic roles of type 1 interferons in antiviral immune responses //Advances in immunology. — Academic Press, 2016. — Vol. 132. — pp. 135–158.

9. Gresser I. On intuition and the discovery of interferon. Cytokine Growth Factor Rev. 2015 Apr;26 (2):99–101. doi: 10.1016/j.cytogfr.2014.11.006. Epub 2014 Nov 22. PubMed PMID: 25547990.

10. Matsuyama N. The dinucleotide microsatellite polymorphism of IFNAR1 gene promoter correlates with responsiveness of hepatitis C patients to interferon. Hepatol. Res. 2003; 25: 221–22510

11. ShanRen, HaibinYu, Hongwei Zhang, Ying Liu, Yanxiang Huang, Lina Ma,. HaoWu. Polymorphisms of interferon-inducible genes OAS associated with interferon-α treatment response in chronic HBV infection. Antiviral Res. 2011; 89: 232–237

12. Persico M. Elevated expression and polymorphisms of SOCS3 influence patient response to antiviral therapy in chronic hepatitis C. Gut. 2008; 57: 507–515

13. Y. Arimori, R. Nakamura, H. Yamada, K. Shibata, N. Maeda, T. Kase. Type I interferon limits influenza virus-induced acute lung injury by regulation of excessive inflammation in mice Antiviral Research, 99 (2013), pp. 230–237

14. Hayden F. G., Fritz R., Lobo M. C., Alvord W., W. Strober S. E., Straus Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense The Journal of clinical investigation, 101 (1998), pp. 643–649

15. Davidson S. Crotta, T. M. McCabe, A. WackPathogenic potential of interferon alphabeta in acute influenza infection Nature Communications, 5 (2014), p. 3864].

16. R. Channappanavar A. R. Fehr, R. Vijay, M. Mack, J. Zhao, D. K. Meyerholz.Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice Cell Host & Microbe, 19 (2016), pp. 181–193

17. Narayanan K. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells J. Virol. 2008; 82: 4471–4479

18. Kamitani W. A two-pronged strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein.Nat. Struct. Mol. Biol. 2009; 16: 1134–1140

19. Ying Li, Chao Li., Peng Xue., Bo Zhong, Ai-Ping Mao, Yong Ran, He Chen, Yan-Yi Wang, Fuquan Yang, and Hong-Bing ShuISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. 05.2009. 106 (19): 7945–50. doI: 10.1073 / pnas.0900818106

20. Ahn J., Xia T., Rabasa A. Capote D. Betancourt G. N. Barber Extrinsic phagocyte-dependent STING signaling dictates the immunogenicity of dying cells Cancer Cell, 33 (2018) 862–873.e5

21. H. Ma, W. Yang, L. Zhang, S. Liu, M. Zhao, G. Zhou, L. Wang, S. Jin, Z. Zhang, J. HuInterferonalpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma Br.J. Cancer, 120 (2019), pp. 317–330

22. Ospelnikova T. P, Noseikina E. M., Gaiderova L. A., Ershov F. I. Therapeutic potential of alphainterferon preparations dur- ing socially significant human diseases of viral etiology. Zh Mikrobiol Epidemiol Immunobiol. 2016 Sep; (5):109–121. Review.Russian

23. FDA. For Industry. Developing products for rare diseases and conditions. http://www.fda.gov/forindustry/DevelopingProductsforrareDiseasesConditions/default.htm. Accessed 15.03.2020

24. https://www.elsevier.com/connect/coronavirus-information-center Accessed 15.03.2020

25. Oshansky, C. M. Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load //American journal of respiratory and critical care medicine. — 2014. — T. 189. no. 4. — P. 449–462].

26. Erman E. S. Efficiency of interferon inductor anaferon (pediatric formulation) in prophylaxis of acute respiratory infections in sickly children //Bulletin of experimental biology and medicine. — 2009. — T. 148. no. 2. — 270 p. 27.

27. Malmo J., Moe N., Krokstad S., Ryan L., Loevenich S., Johnsen I. B., Espevik T, Nordbø S. A., Døllner H., Anthonsen M.W. Cytokine Profiles in Human Metapneumovirus Infected Children: Identification of Genes Involved in the Antiviral Response and Pathogenesis. PLoS One. 2016 May 12;11 (5): e0155484. doi: 10.1371/journal.pone.0155484

28. Nesterova I.V., Kovaleva S.V., Kleshchenko E. I., Chudilova G. A., Lomtatidze L.V., Shinkareva O. N., Parfenov V.V., Koltsov V. D. Optimization of interferon — and immunotherapy tactics in the rehabilitation of immunocompromised children with repeated respiratory and herpetic viral infections. — 2014. — Issue 93 No. 3. — pp. 66–72.

29. Gao L. A randomized controlled trial of low-dose recombinant human interferon alpha-2b nasal spray to prevent acute viral respiratory infections in military recruits. Vaccine. 2010; 28: 4445–4451

30. Berry C. M. Understanding Interferon Subtype Therapy for Viral Infections: Harnessing the Power of the Innate Immune System. Cytokine Growth Factor Rev. 2016 Oct; 31:83–90. doi: 10.1016/j.cytogfr.2016.08.001

31. European Medicines Agency. Committee for medicinal products for human use. Guidelines on the clinical investigation of the pharmacokinetics of therapeutic proteins. 2005.

32. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/ WC500003031.pdf.Accessed 15.03.2020].

33. Poreaux C, Bronowicki J-P, Debouverie M, et al. Managing generalized interferon-induced eruptions and the effectiveness of desensitization. Clin Exp Allergy. 2014; 44:756–764], has minor side effects due to low immunogenicity

34. Baldo B.A. Side effects of cytokines approved for therapy. Drug Saf. 2014 Nov;37 (11):921–43. doi: 10.1007/s40264-014-0226-z

35. Negro F. Adverse effects of drugs in the treatment of viral hepatitis. Best Pract Res Clin Gastroenterol. 2010; 24:183–92.

36. Kraus M.R., Schäfer A., Faller HPsychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry. 2003; 64:708–714

37. Negro F. Adverse effects of drugs in the treatment of viral hepatitis. Best Pract Res Clin Gastroenterol. 2010; 24:183–192

38. FDA. CDER Therapeutic Biologic Products. CDER billable biologic product list. http://www.fda.gov/ drugs/developmentapprovalprocess/druginnovation/default.htm. Accessed 15.03.2020

39. Constant A., Castera L., Dantzer R., Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005;66: 1050–1057

40. Schaefer M., Horn M., Schmidt F., Correlation betweensICAM-1 and depressive symptoms during adjuvant treatment of melanoma with interferon alpha. Brain Behav Immun. 2004;18:555–562.

41. Raison C. L., Demetrashvili M, Capuron L. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005; 19:105–123

42. Bocci V. Pharmacology and side-effects of interferons. Antiviral Res. 1994Jul;24 (2-3):111–119.

43. Vakhitov Kh.M., Pikuza O. I., Vakhitova L. F., Zakirova A.M., Rizvanova F. F. Interferon inducers in the prevention and treatment of respiratory infections in children // Russian Bulletin of Perinatology and Pediatrics. — 2019. — No. 64 (3). — pp. 103–108. https://doi.org/10.21508/1027-4065-2019-6 4-3-103-108

44. Tothova E. Immune-mediated complications during interferon alpha therapy in chronic myelogenous leukemia / / Neoplasma. 2002. Vol. 49. no. 2. pp. 91–94

45. Abbott I. J, Chang C.C., Skinner MJ. Development and management of systemic lupus erythematosus in an HIV-infected man with hepatitis C and B co-infection following interferon therapy: a case report. J. Med Case Rep. 2009; 3:7289

46. Yagyu H., Okada K, Sato S., Pegylated interferon-alpha2b and ribavirin combination therapy induces Hashitoxicosis followed by type 1 diabetes mellitus. Diabetes Res Clin Pract. 2012;95: e52–4.1

47. Pinto JL, Pinto ME. Tiroiditis autoinmune inducida por interferón en pacientes con infección por virus de la hepatitis C [Interferon-induced autoimmune thyroiditis in a patient with hepatitis C virus infection.] Diferencias clínicas y polisomnográficas entre obesos y no obesos con síndrome de apneas-hipopneas del sueño Rey de Castro, Jorge; Rosales-Mayor, Edmundo Rev Peru Med Exp Salud Publica. 2011; 28:382–4.127

48. Agarwal SK, Lal C, Zaidi SH. Lupus activation with cerebritis following pegylated interferon in a hemodialysis patient. Nat.Rev. Nephrol. 2009; 5:599–603

49. Buie J.J. IFN-α negatively regulates the expression of endothelial nitric oxide synthase and nitric oxide production: implications for systemic lupus erythematosus //The Journal of Immunology. — 2017. — Vol. 199. — no. 6. — P. 1979–1988

50. Rebecca L. Casazza, Helen M. Lazar,Jonathan J. Miner Protective and pathogenic effects of Interferon Signaling during pregnancy Published online: January 13, 2020 https://doi.org/10.1089/ vim.2019.0076

51. https://evolve.elsevier.com/cs/store?role=faculty, access time 28.03.20

52. Walbracht A, Treuner T, Flechmig B,Joster KE, Niet Hammerd. Interferon neutralizing antibodies in a patient treated with human fibroblast interferon. Nature 1981; 287:496-8. 2.

53. Mogensen K. E., Dobas R. H., Gresser I., Sereni D., Varet B. Patients with circulating antibodies to interferon.Lancet 1981;2:1227-8.3.

54. J. Quesada. R., Rios, A., Swenson,D., Guterman, H. L., Antitumor activity of recombinant interferon Alfa in metastatic renal-cell carcinoma. J. Clin Oncol1985; 3:1522-1528.4.

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У человека известно 9 видов интерферонов (IFN), объединенных в 3 типа — I, II, III — по способности взаимодействия с соответствующими рецепторами. По образному выражению Н. Zhou, IFN можно рассматривать как «ключ для доступа», а рецептор IFN как «блокировку сигнала доступа», перекрестные реакции и менеджеры поддерживают баланс во время вирусной инфекции [1]. К IFN I относятся IFN-α, IFN-β, -ω, -ε, -ϰ, -τ, имеющие рецептор -IFNAR [2]. IFN II типа представлены IFN-γ (рецепторы IFNGR1 и IFNGR2). IFN типа III (IFN-λ) (рецепторы IFNLR1 и IL10R2) [3].

Вирусы паразитируют на механизме трансляции хозяина, чтобы реплицироваться, и, как следствие, основные пути распознавания, приводящие к IFN типа I, инициируются цитозольными PRR. IFN могут запускать индукцию экспрессии генов, индуцируемых IFN, посредством Jinus kinase (JAK) и сигнальной трансдукции и активаторов транскрипции (STAT), сигнального пути [3].

Активность IFN в организме человека реализуется через противовирусные, иммуномодулирующие, пролиферативные эффекты [4]. В процессе острой и хронической инфекции IFN играют ключевую роль в балансе между противовирусными воспалительными и супрессивными механизмами [5]. Иммуномодулирующий эффект заключается в способности IFN регулировать взаимодействие клеток, участвующих в иммунном ответе, усиливая экспрессию на мембранах клеток молекул MHC I, или в непосредственной активации макрофагов и NK клеток [6]. IFN способны к подавлению роста клеток за счет ингибирования факторов, стимулирующих их пролиферацию [7].

Противовирусное действие IFN определяется подавлением синтеза вирусной РНК, белков оболочки вируса, активацией внутриклеточных ферментов протеинкиназы, который приводит к деструкции фактора инициации синтеза белка с матричной РНК (m-RNA), подавляющий белковый синтез и аденилат-синтетазы, вызывающей синтез веществ, разрушающих вирусную РНК. Под действием IFN происходят изменения рецепции клеточной мембраны, что препятствует адсорбции вируса и пенетрации его в клетку.

Для Цитирования:
Гизингер О.А., Интерфероны и интерферонотерапия. Обзор литературы. Терапевт. 2021;7.
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