A relation between T cell phenotypic profile and virus genotype in patients with chronic viral hepatitis (before and after treatment with direct antiviral agents)

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Abstract

The aim of the study was to investigate the phenotype of effector T lymphocytes in patients with chronic viral hepatitis C (CVHC) before and after of treatment with direct antiviral drugs depending on the genotype of the virus. 50 patients with CVHC without signs of liver cirrhosis were examined. The diagnosis was made on the basis of epidemiological and clinical laboratory data as recommended by the European Association for the Study of the Liver when specific serological markers of CHCV and RNA of hepatitis C virus (HCV) were detected (EASL, 2016). The determination of HCV RNA was carried out by the method of quantitative polymerase chain reaction in real time. The degree of liver fibrosis in patients with CVHC was assessed using ultrasound elastography. Patients were treated for 3 months with direct antiviral drugs according to the recommendations of the European Association for the Study of the Liver (2016). The control group included 46 practically healthy individuals with severe chronic diseases of various organs and systems excluded during a routine examination, no health complaints, having normal clinical and biochemical blood tests in the absence of markers for viral hepatitis B and C, antibodies to opisthorchis and denying history of alcohol abuse. The study of the subpopulation composition of helper and cytotoxic T lymphocytes was carried out by direct immunofluorescence of whole peripheral blood. We obtained a 100% sustained virological response in patients with 1, 2 and genotypes of CHCV without signs of liver cirrhosis when using therapy with Sofosbuvir (400 mg) and Daclatasvir (60 mg) for 12 weeks. It was found that in CVHC patients were found characteristic features in the phenotypic composition of effector T lymphocytes before and after treatment with direct antiviral drugs in depending on the genotype of HCV. Patients with HCV genotypes 1 and 3 had an increase in the content of terminal differentiated effector (TEMRA) T helpers and effector memory (EM). Only patients with HCV genotype 2 had a decrease in the level of EM T-helper cells in the blood. A decrease in the relative number of T helpers of central memory (СM) was independent of the HCV genotype. The level of effector subpopulations of cytotoxic T lymphocytes in patients with CVHC was consistent with or exceeded control levels in depending on the genotype of HCV. The level of all investigated subpopulations of effector cytotoxic T lymphocytes in patients with HCV genotype 1 was equal to the control values. The number of naïve cytotoxic T cells and CM in peripheral blood in patients with HCV genotype 2 was increased. The content of naïve cytotoxic T lymphocytes, CM and TEMRA in patients with genotype 3 HCV in the blood was increased. The highest viral load was detected in patients with CVHC with genotype 1 HCV. Liver fibrosis was most pronounced in patients with CVHC infection with HCV genotypes 2 and 3. After 3 months of treatment with direct antiviral drugs the patients with CVHC had a reduced content of CM T helpers regardless of the HCV genotype. In addition, patients with HCV genotypes 1 and 3 had a decrease in the number of naïve T helpers and patients with HCV genotypes 2 and 3 had a normalization of the content of naïve cytotoxic T lymphocytes.

About the authors

A. A. Savchenko

Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North

Email: aasavchenko@yandex.ru

PhD, MD (Medicine), Professor, Head of the Laboratory of Cellular-Molecular Physiology and Pathology, Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North.

Krasnoyarsk.

Россия

V. V. Tsukanov

Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North

Email: aasavchenko@yandex.ru

PhD, MD (Medicine), Professor, Head of the Clinical Department of Digestive System Pathology, Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North.

Krasnoyarsk.

Россия

I. V. Kudryavtsev

Institute of Experimental Medicine; Pavlov First Saint Petersburg State Medical University

Author for correspondence.
Email: igorek1981@yandex.ru

Igor V. Kudryavtsev - PhD (Biology), Head of the Cell Immunology Laboratory, Department of Immunology, Institute of Experimental Medicine; Assistant Professor, Department of Immunology, Pavlov First Saint Petersburg State Medical University.

197376, St. Petersburg, Academician Pavlov str., 12.

Phone: +7 812 234-29-29

Россия

J. L. Tonkih

Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North

Email: aasavchenko@yandex.ru

PhD (Medicine), Leading Researcher, Clinical Department of Digestive System Pathology, Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North.

Krasnoyarsk.

Россия

V. D. Belenjuk

Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North

Email: dyh.88@mail.ru

Junior Researcher, Laboratory of Cellular-Molecular Physiology and Pathology, Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North.

Krasnoyarsk.

Россия

M. A. Cherepnin

Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North

Email: fake@neicon.ru

Junior Researcher, Clinical Department of Digestive System Pathology, Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North.

Krasnoyarsk.

Россия

A. A. Anisimova

Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North

Email: fake@neicon.ru

Junior Researcher, Clinical Department of Digestive System Pathology, Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North.

Krasnoyarsk.

Россия

A. G. Borisov

Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North

Email: 2410454@mail.ru

PhD (Medicine), Leading Researcher, Laboratory of Cellular-Molecular Physiology and Pathology, Krasnoyarsk Research Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North.

Krasnoyarsk.

Россия

References

  1. Борисов А.Г., Савченко А.А., Кудрявцев И.В. Особенности иммунного реагирования при вирусных инфекциях // Инфекция и иммунитет. 2015. Т. 5, № 2. С. 148–156. doi: 10.15789/2220-7619-2015-2-148-156
  2. Борисов А.Г., Савченко А.А., Тихонова Е.П. Современные методы лечения вирусного гепатита C. Красноярск: НИИ медицинских проблем Севера, 2017. 74 с.
  3. Елезов Д.С., Кудрявцев И.В., Арсентьева Н.А., Семенов А.В., Эсауленко Е.В., Басина В.В., Тотолян А.А. Анализ субпопуляций Т-хелперов периферической крови больных хроническим вирусным гепатитом С, экспрессирующих хемокиновые рецепторы CXCR3 и CCR6 и активационные маркеры CD38 и HLA-DR // Инфекция и иммунитет. 2013. Т. 3, № 4. С. 327–334. doi: 10.15789/2220-7619-2013-4-327-334
  4. Зурочка А.В., Хайдуков С.В., Кудрявцев И.В., Черешнев В.А. Проточная цитометрия в биомедицинских исследованиях. Екатеринбург: Уральское отделение РАН, 2018. 720 с.
  5. Кудрявцев И.В., Борисов А.Г., Васильева Е.В., Кробинец И.И., Савченко А.А., Серебрякова М.К., Тотолян Арег А. Фенотипическая характеристика цитотоксических Т-лимфоцитов: регуляторные и эффекторные молекулы // Медицинская иммунология. 2018. Т. 20, № 2. С. 227–240. doi: 10.15789/1563-0625-2018-2-227-240
  6. Кудрявцев И.В., Борисов А.Г., Кробинец И.И., Савченко А.А., Серебрякова М.К. Определение основных субпопуляций цитотоксических Т-лимфоцитов методом многоцветной проточной цитометрии // Медицинская иммунология. 2015, Т. 17, № 6. С. 525–538. doi: 10.15789/1563-0625-2015-6-525-538
  7. Кудрявцев И.В., Субботовская А.И. Опыт измерения параметров иммунного статуса с использованием шестицветного цитофлуориметрического анализа // Медицинская иммунология. 2015. Т. 17, № 1. С. 19–26. doi: 10.15789/1563-0625-2015-1-19-26
  8. Орлова С.Н., Басханова М.В. Эффективность противовирусной терапии хронического гепатита С у пациентов с недифференцированной дисплазией соединительной ткани // Эпидемиология и инфекционные болезни. 2019. № 2. С. 61–67. doi: 10.18565/epidem.2019. 2.61-67
  9. Щаницына С.Е., Бурневич Э.З., Никулкина Е.Н., Филатова А.Л., Моисеев С.В., Мухин Н.А. Факторы риска неблагоприятного прогноза хронического гепатита С // Терапевтический архив. 2019. Т. 91, № 2. С. 59–66. doi: 10.26442/00403660.2019.02.000082
  10. Южанинова С.В., Сайдакова Е.В. Феномен иммунного истощения // Успехи современной биологии. 2017. Т. 137, № 1. С. 70–83.
  11. Ярилин А.А. Иммунология. М.: ГЭОТАР-Медиа, 2010. 752 с.
  12. Ahmed M. Era of direct acting anti-viral agents for the treatment of hepatitis C. World J. Hepatol., 2018, vol. 10, no. 10, pp. 670– 684. doi: 10.4254/wjh.v10.i10.670
  13. Aregay A., Owusu Sekyere S., Deterding K., Port K., Dietz J., Berkowski C., Sarrazin C., Manns M.P., Cornberg M., Wedemeyer H. Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell responses. J. Hepatol., 2019, vol. 71, no. 5, pp. 889–899. doi: 10.1016/j.jhep.2019.06.025
  14. Barathan M., Mohamed R., Yong Y.K., Kannan M., Vadivelu J., Saeidi A., Larsson M., Shankar E.M. Viral persistence and chronicity in hepatitis C virus infection: role of T-cell apoptosis, senescence and exhaustion. Cells, 2018, vol. 7, no. 10: E165. doi: 10.3390/cells7100165
  15. Ben A.J., Neumann C.R., Mengue S.S. The brief medication questionnaire and Morisky–Green test to evaluate medication adherence. Rev. Saude Publica, 2012, vol. 46, no. 2, pp. 279–289. doi: 10.1590/s0034-89102012005000013
  16. Cuypers L., Ceccherini-Silberstein F., Van Laethem K., Li G., Vandamme A.M., Rockstroh J.K. Impact of HCV genotype on treatment regimens and drug resistance: a snapshot in time. Rev. Med. Virol., 2016, vol. 26, no. 6, pp. 408–434. doi: 10.1002/rmv.1895
  17. Deming P., Martin M.T., Chan J., Dilworth T.J., El-Lababidi R., Love B.L., Mohammad R.A., Nguyen A., Spooner L.M., Wortman S.B. Therapeutic advances in HCV genotype 1 infection: insights from the society of infectious diseases pharmacists. Pharmacotherapy, 2016, vol. 36, no. 2, pp. 203–217. doi: 10.1002/phar.1700
  18. EASL recommendations on treatment of hepatitis C 2016. J. Hepatol., 2017, vol. 66, no. 1, pp. 153–194. doi: 10.1016/j.jhep.2016.09.001
  19. EASL recommendations on treatment of hepatitis C 2018. J. Hepatol., 2018, vol. 69, no. 2, pp. 461–511. doi: 10.1016/j.jhep.2018.03.026
  20. Egui A., Ledesma D., Pérez-Antón E., Montoya A., Gómez I., Robledo S.M., Infante J.J., Vélez I.D., López M.C., Thomas M.C. Phenotypic and functional profiles of antigen-specific CD4(+) and CD8(+) T Cells associated with infection control in patients with cutaneous leishmaniasis. Front. Cell Infect. Microbiol., 2018, vol. 8: 393. doi: 10.3389/fcimb.2018.00393
  21. Ghany M.G., Morgan T.R.; AASLD-IDSA Hepatitis C Guidance Panel. Hepatitis C Guidance 2019 Update: American Association for the study of Liver Diseases-Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology, 2020, vol. 71, no. 2, pp. 686–721. doi: 10.1002/hep.31060
  22. Lin M., Kramer J., White D., Cao Y., Tavakoli-Tabasi S., Madu S., Smith D., Asch S.M., El-Serag H.B., Kanwal F. Barriers to hepatitis C treatment in the era of direct-acting anti-viral agents. Aliment Pharmacol. Ther., 2017, vol. 46, no. 10, pp. 992–1000. doi: 10.1111/apt.14328
  23. Luxenburger H., Neumann-Haefelin C., Thimme R., Boettler T. HCV-specific T cell responses during and after chronic HCV infection. Viruses, 2018, vol. 10, no. 11: E645. doi: 10.3390/v10110645
  24. Mangare C., Tischer-Zimmermann S., Riese S.B., Dragon A.C., Prinz I., Blasczyk R., Maecker-Kolhoff B., Eiz-Vesper B. Robust identification of suitable T-cell subsets for personalized CMV-specific T-cell immunotherapy using CD45RA and CD62Lmicro-beads. Int. J. Mol. Sci., 2019, vol. 20, no. 6: E1415. doi: 10.3390/ijms20061415
  25. Modin L., Arshad A., Wilkes B., Benselin J., Lloyd C., Irving W.L., Kelly D.A. Epidemiology and natural history of hepatitis C virus infection among children and young people. J. Hepatol., 2019, vol. 70, no. 3, pp. 371–378. doi: 10.1016/j.jhep.2018.11.013
  26. Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol. Hepatol., 2017, vol. 2, no. 3, pp. 161–176. doi: 10.1016/S2468-1253(16)30181-9
  27. Saeidi A., Zandi K., Cheok Y.Y., Saeidi H., Wong W.F., Lee C.Y.Q., Cheong H.C., Yong Y.K., Larsson M., Shankar E.M. T-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective immune responses. Front. Immunol., 2018, vol. 9: 2569. doi: 10.3389/fimmu.2018.02569
  28. Stevenson T.J., Barbour Y., McMahon B.J., Townshend-Bulson L., Hewitt A.M., Espera H.G.F., Homan C., Holck P., Luna S.V., Knall C., Simons B.C. Observed changes in natural killer and T cell phenotypes with evaluation of Immune outcome in a longitudinal cohort following Sofosbuvir-based therapy for chronic hepatitis C infection. Open Forum Infect. Dis., 2019, vol. 6, no. 6: ofz223. doi: 10.1093/ofid/ofz223
  29. Sutherland D.R., Ortiz F., Quest G., Illingworth A., Benko M., Nayyar R., Marinov I. High-sensitivity 5-, 6-, and 7-color PNH WBC assays for both Canto II and Navios platforms. Cytometry B Clin. Cytom., 2018, vol. 94, no. 4, pp. 637–651. doi: 10.1002/cyto.b.21626
  30. Telatin V., Nicoli F., Frasson C., Menegotto N., Barbaro F., Castelli E., Erne E., Palù G., Caputo A. in chronic hepatitis C infection, myeloid-derived suppressor cell accumulation and T cell dysfunctions revert partially and late after successful direct-acting antiviral treatment. Front. Cell Infect. Microbiol., 2019, vol. 9: 190. doi: 10.3389/fcimb.2019.00190
  31. Valadkhan S., Fortes P. Regulation of the interferon response by lncRNAs in HCV infection. Front. Microbiol. 2018, vol. 9: 181. doi: 10.3389/fmicb.2018.00181
  32. Weltevrede M., Eilers R., de Melker H.E., van Baarle D. Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: a systematic review. Exp. Gerontol., 2016, vol. 77, pp. 87–95. doi: 10.1016/j.exger.2016.02.005
  33. Younossi Z., Papatheodoridis G., Cacoub P., Negro F., Wedemeyer H., Henry L., Hatzakis A. The comprehensive outcomes of hepatitis C virus infection: a multi-faceted chronic disease. J. Viral. Hepat., 2018, vol. 25, no. 3, pp. 6–14. doi: 10.1111/jvh.13005
  34. Zhao J., Dang X., Zhang P., Nguyen L.N., Cao D., Wang L., Wu X., Morrison Z.D., Zhang Y., Jia Z., Xie Q., Wang L., Ning S., El Gazzar M., Moorman J.P., Yao Z.Q. Insufficiency of DNA repair enzyme ATM promotes naive CD4 T-cell loss in chronic hepatitis C virus infection. Cell Discov., 2018, vol. 4: 16. doi: 10.1038/s41421-018-0015-4

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Copyright (c) 2021 Savchenko A.A., Tsukanov V.V., Kudryavtsev I.V., Tonkih J.L., Belenjuk V.D., Cherepnin M.A., Anisimova A.A., Borisov A.G.

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