Immunopathogenesis and perspectives for immunotherapy of coronavirus infection

Симбирцев А. С.

Статья

Иммунопатогенез и перспективы иммунотерапии коронавирусной инфекции

Симбирцев А. С.,

2021

https://doi.org/10.22328/2077-9828-2020-12-4-7-22

Инфицирование высокопатогенным коронавирусом SARS-CoV-2 в ряде случаев приводит к развитию тяжелого вирусного заболевания (COVID-19), иногда со смертельным исходом. Иммунопатогенез COVID-19 связан с развитием несбалансированного иммунного ответа на вирус с недостаточным синтезом интерферона в начале заболевания, но с последующей гиперпродукцией провоспалительных цитокинов, служащей причиной неадекватно сильного воспаления в легочной ткани с развитием острого поражения легких и респираторного дистресс-синдрома. Перспективными направлениями иммунотерапии COVID-19 могут быть: лечение препаратами интраназального рекомбинантного интерферона в начальной стадии инфекционного процесса, применение антицитокиновой терапии при развитии тяжелой пневмонии и цитокинового шторма, пассивная иммунизация с использование плазмы крови переболевших пациентов и препаратов терапевтических моноклональных антител, профилактическая вакцинация.

Цитирование

Список литературы

1. Wu F., Zhao S., Yu B., Chen Y.M., Wang W., Song Z.G. A new coronavirus associated with human respiratory disease in China // Nature. 2020. Vol. 579 (7798). P. 265–269. doi: 10.1038/s41586-020-2008-3.

2. Chen N., Zhou M., Dong X. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study // Lancet. 2020. Vol. 395 (10223). P. 507–513. doi: 10.1016/S0140-6736(20)30211-7.

3. Huang C., Wang Y., Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China // Lancet. 2020. Vol. 395 (10223). P. 497–506. doi: 10.1016/S0140-6736(20)30183-5.

4. Xu Z., Shi L., Wang Y. et al. Pathological ﬁndings of COVID-19 associated with acute respiratory distress syndrome // Lancet Respir. Med. 2020. Vol. 8 (4). P. 420–422. doi: 10.1016/S2213-2600(20)30076-X.

5. Ou X., Liu Y., Lei X. et al. Characterization of Spike Glycoprotein of SARS-CoV-2 on Virus Entry and Its Immune Cross-Reactivity With SARSCoV // Nat. Commun. 2020. Vol. 11 (1). P. 1620. doi: 10.1038/s41467-020-15562-9.

6. Zhou P., Yang X., Wang X. A pneumonia outbreak associated with a new coronavirus of probable bat origin // Nature. 2020. Vol. 579 (7798). P. 270–273. doi: 10.1038/s41586-020-2012-7.

7. Ulrich H., Pillat M. CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement // Stem Cell Rev Rep. 2020. Apr. 20. doi: 10.1007/s12015-020-09976-7. Online ahead of print.

8. Wang Q., Zhang Y., Wu L. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2 // Cell. 2020. Vol. 181. P. 1–11. https://doi.org/10.1016/j.cell.2020.03.045

9. Takeuchi O., Akira S. Pattern recognition receptors and inﬂammation // Cell. 2010. Vol. 140 (6). P. 805–820. doi: 10.1016/j.cell.2010.01.022.

10. Jefferies C. Regulating IRFs in IFN Driven Disease // Front. Immunol. 2019. Vol. 10. P. 325. doi: 10.3389/ﬁmmu.2019.00325.

11. Mitchell S., Mercado E., Adelaja A. An NFkB Activity Calculator to Delineate Signaling Crosstalk: Type I and II Interferons Enhance NFkB via Distinct Mechanisms // Front. Immunol. 2019. Vol. 10. P. 1425. doi: 10.3389/ﬁmmu.2019.01425.

12. Zhu X., Wang Y., Zhang H. Genetic variation of the human alpha-2-Heremans-Schmid glycoprotein (AHSG) gene associated with the risk of SARS-CoV infection // PloS One. 2011. Vol. 6 (8). P. e23730. doi: 10.1371/journal.pone.0023730.

13. Ivashkiv L., Donlin L. Regulation of type I interferon responses // Nature reviews Immunology. 2014. Vol. 14 (1). P. 36–49. doi: 10.1038/nri3581.

14. Pestka S., Krause C., Walter M. Interferons, interferon-like cytokines, and their receptors // Immunol. Rev. 2004. Vol. 202. P. 8–32. doi: 10.1111/j.0105-2896.2004.00204.x.

15. Kotenko S., Gallagher G., Baurin V. IFN lambdas mediate antiviral protection through a distinct class II cytokine receptor complex // Nat. Immunol. 2003. Vol. 4 (1). P. 69–77. doi: 10.1038/ni875.

16. Prejean C., Colamonici O. Role of the cytoplasmic domains of the type I interferon receptor subunits in signaling // Seminars in Cancer Biology. 2000. Vol. 10 (2). P. 83–92. doi: 10.1006/scbi.2000.0311.

17. Schoggins J., Wilson S., Panis M. A diverse range of gene products are effectors of the type I interferon antiviral response // Nature. 2011. Vol. 472 (7344). P. 481–485. doi: 10.1038/nature09907.

18. Ye L., Schnepf D., Staeheli P. Interferon- l orchestrates innate and adaptive mucosal immune responses // Nat. Rev. Immunol. 2019. Vol. 19 (10). P. 614–625. doi: 10.1038/s41577-019-0182-z.

19. Fairman P., Angel J. The effect of human immunodeﬁciency virus-1 on monocyte-derived dendritic cell maturation and function // Clinical and experimental immunology. 2012. Vol. 170 (1). P. 101–113. doi: 10.1111/j.1365-2249.2012.04628.x.

20. Cardone M., Ikeda K., Varano B., Gessani S., Conti L. HIV-1-induced impairment of dendritic cell cross talk with gammadelta T lymphocytes // Journal of virology. 2015. Vol. 89 (9). P. 4798–4808. doi: 10.1128/JVI.03681-14.

21. Shokri S., Mahmoudvand S., Taherkhani R., Farshadpour F. Modulation of the immune response by Middle East respiratory syndrome coronavirus // J. Cell. Physiol. 2019. Vol. 234 (3). P. 2143–2151. doi: 10.1002/jcp.27155.

22. Schulz K., Mossman K. Viral Evasion Strategies in Type I IFN Signaling — A Summary of Recent Developments // Front. Immunol. 2016. Vol. 7. P. 498. doi: 10.3389/ﬁmmu.2016.00498.

23. Spiegel M., Pichlmair A., Martinez-Sobrido L. et al. Inhibition of Beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3 // Journal of virology. 2005. Vol. 79 (4). P. 2079–2086. doi: 10.1128/JVI.79.4.2079-2086.2005.

24. Kopecky-Bromberg S., Martinez-Sobrido L., Frieman M., Baric R., Palese P. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists // Journal of virology. 2007. Vol. 81 (2). P. 548–557. doi: 10.1128/JVI.01782-06.

25. Lu X., Pan J., Tao J., Guo D. SARS-CoV nucleocapsid protein antagonizes IFN-beta response by targeting initial step of IFN-beta induction pathway, and its C-terminal region is critical for the antagonism // Virus genes. 2011. Vol. 42 (1). P. 37–45. doi: 10.1007/s11262-010-0544-x.

26. Kindler E., Thiel V., Weber F. Interaction of SARS and MERS Coronaviruses with the Antiviral Interferon Response // Adv. Virus Res. 2016. Vol. 96. P. 219–243. doi: 10.1016/bs.aivir.2016.08.006.

27. de Wit E., van Doremalen N., Falzarano D., Munster V. SARS and MERS: recent insights into emerging coronaviruses // Nat. Rev. Microbiol. 2016. Vol. 14 (8). P. 523–534. doi: 10.1038/nrmicro.2016.81.

28. Kikkert M. Innate Immune Evasion by Human Respiratory RNA Viruses // J. Innate Immun. 2020. Vol. 12 (1). P. 4–20. doi: 10.1159/000503030.

29. Faure E., Poissy J., Goffard A. Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? // PLoS One. 2014. Vol. 9 (2). e88716. doi: 10.1371/journal.pone.0088716.

30. Channappanavar R., Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology // Semin Immunopathol. 2017. Vol. 39 (5). P. 529–539. doi: 10.1007/s00281-017-0629-x.

31. Lessler J., Reich N., Brookmeyer R. Incubation periods of acute respiratory viral infections: a systematic review // Lancet Infect. Dis. 2009. Vol. 9 (5). P. 291–300. doi: 10.1016/S1473-3099(09)70069-6.

32. Channappanavar R., Fett C., Zhao J., Meyerholz D., Perlman S. Virus-speciﬁc memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection // J. Virol. 2014. Vol. 88 (19). P. 11034–11044. doi: 10.1128/JVI.01505-14.

33. Zhao J., Li K., Wohlford-Lenane C. et al. Rapid generation of a mouse model for Middle East respiratory syndrome // Proc. Natl. Acad. Sci. USA. 2014. Vol. 111 (13). P. 4970–4975. doi: 10.1073/pnas.1323279111.

34. Maloir Q., Ghysen K., von Frenckell C., Louis R., Guiot J. [Acute respiratory distress revealing antisynthetase syndrome] // Revue medicale de Liege. 2018. Vol. 73 (7–8). P. 370–375. PMID: 30113776.

35. Yang Y., Xiong Z., Zhang S. Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors // Biochem. J. 2005. Vol. 392 (Pt 1). P. 135–143. doi: 10.1042/BJ20050698.

36. Mubarak A., Alturaiki W., Hemida M. Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Infection, Immunological Response, and Vaccine Development // J. Immunol. Res. 2019. Vol. 2019. P. 6491738. doi: 10.1155/2019/6491738.

37. Chen J., Lau Y., Lamirande E. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection // J. Virol. 2010. Vol. 84 (3). P. 1289–1301. doi: 10.1128/JVI.01281-09.

38. Li C., Wu H., Yan H. T cell responses to whole SARS coronavirus in humans // J. Immunol. 2008. Vol. 181 (8). P. 5490–5500. doi: 10.4049/jimmunol.181.8.5490.

39. Liu W., Fontanet A., Zhang P. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome // J. Infect. Dis. 2006. Vol. 193 (6). P. 792–795. doi: 10.1086/500469.

40. Niu P., Zhang S., Zhou P. Ultrapotent Human Neutralizing Antibody Repertoires Against Middle East Respiratory Syndrome Coronavirus From a Recovered Patient // J. Infect. Dis. 2018. Vol. 218 (8). P. 1249–1260. doi: 10.1093/infdis/jiy311.

41. Liu W., Zhao M., Liu K. T-cell immunity of SARS-CoV: Implications for vaccine development against MERS-CoV // Antiviral Res. 2017. Vol. 137. P. 82–92. doi: 10.1016/j.antiviral.2016.11.006.

42. Thevarajan I., Nguyen T., Koutsakos M. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19 // Nat. Med. 2020. Vol. 26. P. 453–455. https://doi.org/10.1038/s41591-020-0819-2.

43. Zhao J., Yuan Q., Wang H. Antibody responses to SARS- CoV-2 in patients of novel coronavirus disease 2019 // Clin. Infect. Dis. 2020. Mar. 28. ciaa344. doi: 10.1093/cid/ciaa344. Online ahead of print.

44. Huang K., Su I.-J., Theron M. An interferon-gamma-related cytokine storm in SARS patients // J. Med. Virol. 2005. Vol. 75 (2). P. 185–194. doi: 10.1002/jmv.20255.

45. Qin C., Zhou L., Hu Z. et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China // Clin. Infect. Dis. 2020. Mar. 12. ciaa248. doi: 10.1093/cid/ciaa248.

46. Wong C., Lam C., Wu A. et al. Plasma inﬂammatory cytokines and chemokines in severe acute respiratory syndrome // Clin. Exp. Immunol. 2004. Vol. 136 (1). P. 95–103 doi: 10.1111/j.1365-2249.2004.02415.x.

47. Mahallawi W., Khabour O., Zhang Q., Makhdoum H., Suliman B. MERS-CoV infection in humans is associated with a pro-inﬂammatory Th1 and Th17 cytokine proﬁle // Cytokine. 2018. Vol. 104. P. 8–13. doi: 10.1016/j.cyto.2018.01.025.

48. Nicholls J., Poon L., Lee K. Lung pathology of fatal severe acute respiratory syndrome // Lancet. 2003. Vol. 361 (9371). P. 1773–1778. doi: 10.1016/S0140-6736(03)13413-7.

49. Gu J., Gong E., Zhang B. et al. Multiple organ infection and the pathogenesis of SARS // J. Exp. Med. 2005. Vol. 202 (3). P. 415–424. doi: 10.1084/jem.20050828.

50. Li T., Qiu Z., Zhang L. et al. Signiﬁcant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome // J. Infect. Dis. 2004. Vol. 189 (4). P. 648–651. doi: 10.1086/381535.

51. Channappanavar R., Fehr A., Vijay R. Dysregulated type I interferon and inﬂammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice // Cell Host Microbe. 2016. Vol. 19 (2). P. 181–193. doi: 10.1016/j.chom.2016.01.007.

52. Cameron M., Xu L., Danesh A. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome // J. Virol. 2007. Vol. 81 (16). P. 8692–8706. doi: 10.1128/JVI.00527-07.

53. Smits S., Lang A., van den Brand J. et al. Exacerbated innate host response to SARS-CoV in aged non-human primates // PLoS Pathog. 2010. Vol. 6 (2). e1000756. doi: 10.1371/journal.ppat.1000756.

54. Rockx B., Baas T., Zornetzer G. et al. Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection // J. Virol. 2009. Vol. 83 (14). P. 7062–7074. doi: 10.1128/JVI.00127-09.

55. Wong J., Viswanathan S., Wang M. Current and future developments in the treatment of virus-induced hypercytokinemia // Future Med. Chem. 2017. Vol. 9 (2). P. 169–178. doi: 10.4155/fmc-2016-0181.

56. Teijaro J., Walsh K., Rice S. Mapping the innate cascade essential for cytokine storm during inﬂuenza virus infection // Proc. Natl. Acad. Sci. USA. 2014. Vol. 111 (10). P. 3799–3804. doi: 10.1073/pnas.1400593111.

57. Gao R., Bhatnagar J., Blau D. et al. Cytokine and chemokine proﬁles in lung tissues from fatal cases of 2009 pandemic inﬂuenza A (H1N1): role of the host immune response in pathogenesis // Am. J. Pathol. 2013. Vol. 183 (4). P. 1258–1268. doi: 10.1016/j.ajpath.2013.06.023.

58. Thomas M., Mani R., Philip M. Proinﬂammatory chemokines are major mediators of exuberant immune response associated with inﬂuenza A (H1N1) pdm09 virus infection // J. Med. Virol. 2017. Vol. 89 (8). P. 1373–1381. doi: 10.1002/jmv.24781.

59. Betáková T., Kostrabova A., Lachova V., Turianova L. Cytokines induced during inﬂuenza virus infection // Curr. Pharm. Des. 2017. Vol. 23 (18). P. 2616–2622. doi: 10.2174/1381612823666170316123736.

60. To K., Hung I., Li I. et al. Delayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 2009 inﬂuenza virus infection // Clin. Infect. Dis. 2010. Vol. 50 (6). P. 850–859. doi: 10.1086/650581.

61. Hayden F., Fritz R., Lobo M. Local and systemic cytokine responses during experimental human inﬂuenza A virus infection. Relation to symptom formation and host defense // J. Clin. Invest. 1998. Vol. 101 (3). P. 643–649. doi: 10.1172/JCI1355.

62. Yu L., Wang Z., Chen Y. Clinical, virological, and histopathological manifestations of fatal human infections by avian inﬂuenza A(H7N9) virus // Clin. Infect. Dis. 2013. Vol. 57 (10). P. 1449–1457. doi: 10.1093/cid/cit541.

63. Bohmwald K., Gálvez N., Canedo-Marroquín G. Contribution of Cytokines to Tissue Damage During Human Respiratory Syncytial Virus Infection // Front Immunol. 2019. Vol. 10. P. 452. doi: 10.3389/ﬁmmu.2019.00452.

64. Zhao J., Yang Y., Huang H. Relationship between the ABO Blood Group and the COVID-19 Susceptibility // MedRxiv 2020.03.11.20031096. doi: 10.1101/2020.03.11.20031096.

65. Liu W., Li H. COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism // Chem. Rxiv. 2020. Preprint. doi: 10.26434/chemrxiv.11938173.v6.

66. Zhang L, Liu Y. Potential interventions for novel coronavirus in China: a systemic review // J. Med. Virol. 2020. Vol. 92 (5). P. 479–490. doi: 10.1002/jmv.25707.

67. De Clercq E., Li G. Approved antiviral drugs over the past 50 years // Clin. Microbiol. Rev. 2016. Vol. 29 (3). P. 695–747. doi: 10.1128/CMR.00102-15.

68. Zumla A., Rao M., Wallis R.S. Host-directed therapies for infectious diseases: current status, recent progress, and future prospects // Lancet. 2016. Vol. 16 (4). e47–63. doi: 10.1016/S1473-3099(16)00078-5.

69. Kaufmann S., Dorhoi A., Hotchkiss R., Bartenschlager R. Host-directed therapies for bacterial and viral infections // Nat. Rev. Drug. Disc. 2018. Vol. 17 (1). P. 35–56. doi: 10.1038/nrd.2017.162.

70. Falzarano D., de Witt E., Rasmussen A. et al. Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques // Nat. Med. 2013. Vol. 19 (10). P. 1313–1317. doi: 10.1038/nm.3362.

71. Дерябин П.Г., Зарубаев В.В. К вопросу о коронавирусной инфекции и перспективах профилактики и лечения препаратами интерферона альфа-2b человеческого рекомбинантного // Инфекционные болезни. 2014. Т. 12, № 3. С. 32–34.

72. Tyrrell D. The efficacy and tolerance of intranasal interferons: studies at the Common Cold Unit // J. Antimicrob. Chemother. 1986. Vol. 18, Suppl B. P. 153–156. doi: 10.1093/jac/18.supplement_b.153.

73. Omrani A., Saad M., Baig K. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study // Lancet Infect Dis. 2014. Vol. 14 (11). P. 1090–1095. doi: 10.1016/S1473-3099(14)70920-X.

74. Zumla A., Chan J., Azhar E. Coronaviruses — drug discovery and therapeutic options // Nat. Rev. Drug Discov. 2016. Vol. 15 (5). P. 327–347 doi: 10.1038/nrd.2015.37.

75. Dong L., Hu S., Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19) // Drug Discoveries & Therapeutics. 2020. Vol. 14 (1). P. 58–60. doi: 10.5582/ddt.2020.01012.

76. Mair-Jenkins J., Saavedra-Campos M., Baillie J. et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis // J. Infect. Dis. 2015. Vol. 211 (1). P. 80–90. doi: 10.1093/infdis/jiu396.

77. Shanmugaraj B., Siriwattananon K., Wangkanont K., Phoolcharoen W. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19) // Asian. Pac. J. Allergy Immunol. 2020. Vol. 38 (1). P. 10–18. doi: 10.12932/AP-200220-0773.

78. Coughlin M., Prabhakar B. Neutralizing human monoclonal antibodies to Severe acute respiratory syndrome coronavirus: target, mechanism of action and therapeutic potential // Rev. Med. Virol. 2012. Vol. 22 (1). P. 2–17. doi: 10.1002/rmv.706.

79. Niu P., Zhao G., Deng Y. A novel human mAb (MERS-GD27) provides prophylactic and postexposure efficacy in MERS-CoV susceptible mice // Science China Life sciences. 2018. Vol. 61 (10). P. 1280–1282. doi: 10.1007/s11427-018-9343-8.

80. Ying T., Du L., Ju T. Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies // J. Virol. 2014. Vol. 88 (14). P. 7796–7805. doi: 10.1128/JVI.00912-14.

81. Houser K., Gretebeck L., Ying T. et al. Prophylaxis With a Middle East Respiratory Syndrome Coronavirus (MERS-CoV)-Speciﬁc Human Monoclonal Antibody Protects Rabbits From MERS-CoV Infection // J. Infect. Dis. 2016. Vol. 213 (10). P. 1557–1561. doi: 10.1093/infdis/jiw080.

82. van Doremalen N., Falzarano D., Ying T. Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERSCoV) in common marmosets // Antiviral Res. 2017. Vol. 143. P. 30–37. doi: 10.1016/j.antiviral.2017.03.025.

83. Ahmed S., Quadeer A., McKay M. Preliminary Identiﬁcation of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies // Viruses. 2020. Vol. 12 (3). P. 254. doi: 10.3390/v12030254.

84. Prompetchara E., Ketloy C., Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic // Asian Pac. J. Allergy Immunol. 2020. Vol. 38 (1). P. 1–9. doi: 10.12932/AP-200220-0772.

85. Du L., He Y., Zhou Y. et al. The spike protein of SARS-CoV — a target for vaccine and therapeutic development // Nat. Rev. Microbiol. 2009. Vol. 7 (3). Р. 226–236. doi: 10.1038/nrmicro2090.

86. Al-Amri S., Abbas A., Siddiq L. et al. Immunogenicity of Candidate MERS-CoV DNA Vaccines Based on the Spike Protein // Sci Rep. 2017. Vol. 7. P. 44875. doi: 10.1038/srep44875.

87. Ng O., Chia A., Tan A. Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection // Vaccine. 2016. Vol. 34 (17). P. 2008–2014. doi: 10.1016/j.vaccine.2016.02.063.

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Симбирцев А. С.
Государственный научно-исследовательский институт особо чистых биопрепаратов Федерального медико-биологического агентства

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COVID-19

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HIV Infection and Immunosuppressive Disorders

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Иммунопатогенез и перспективы иммунотерапии коронавирусной инфекции

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