FELV-ИНФЕКЦИЯ: ПРОБЛЕМЫ И ПЕРСПЕКТИВЫ ВАКЦИНОПРОФИЛАКТИКИ И ИНТЕРФЕРОНО-ТЕРАПИИ ЛЕЙКОЗА КОШЕК

Обзор посвящен оценке эффективности применения препаратов интерферона и индукторов его биосинтеза для лечения лейкоза кошек, а также – разработке методических подходов для повышения эффективности методов интерферонотерапии. Лейкоз кошачьих - это системное злокачественное заболевание крови вирусной природы, заканчивающееся летальным исходом в сроки примерно до 3 лет после инфицирования. Этиологический агентом, вызывающий это заболевание, является одноцепочечным  РНК-содержащим ретровирусом Feline leukemia virus (FeLV). FelV широко распространен в популяциях домашних кошек всех стран, а также нередко выявляется и в крови диких кошек, в том числе - представителей редких и исчезающих видов семейства кошачьих.  В некоторых регионах распространенность FeLV может быть значительной не только среди домашних кошек, но и среди диких. В настоящее время существует несколько коммерчески доступных вакцинных препаратов для защиты кошек от FeLV-инфекции (например, инактивированные цельновирионные вакцины типа Nobivac feline 2-FeLV с адъювантом, двух-адъвантная субъединичая вакцина на основе белковых антигенов возбудителя и безадъювантная векторная ДНК вакцина. Однако ни одна из существующих вакцин не обеспечивает надежную защиту от этого вируса. Кроме того, вакцинация кошек против FeLV нередко сопряжена с развитием разнообразных осложнений воспалительного, аллергического характера, шоковых реакций и даже таких крайне серьезных побочных эффектов как развитие вакцин-ассоциированной саркомы в месте инъекции, что некоторые авторы связывают с применением адъювантов типа солей алюминия и др.

В данном обзоре дается краткая характеристика вируса FeLV, элементы патогенеза ассоциированных с FeLV-инфекцией патологических состояний, а также - современных технологий профилактики и лечения лейкоза кошек. Дается оценка истории и современного состояния интерферонотерапии FeLV-инфекции и связанных с ней неопластических процессов у домашних кошек и некоторых диких видов семейства кошачьих. Рассматриваются возможные мероприятия, направленные на повышение эффективности интерфероно-терапии лейкоза кошек на основе применения новых препаратов рекомбинантного интерферона различных типов и подтипов, а также – индукторов интерферона. В заключении отмечается, что еще одним интересным и потенциально очень перспективным выбором при определении стратегии биотерапии, связанной с модуляцией системы IFN  в организме животных, пораженных FeLV-инфекцией, является применение индукторов образования эндогенного IFN.

1. a. Abraham S, Choi JG, Ortega NM, Zhang J, Shankar P, Swamy NM. Gene therapy with plasmids encoding IFN-β or IFN-α14 confers long-term resistance to HIV-1 in humanized mice. Oncotarget, 2016, Vol. 7, pp.78412-78420. doi: 10.18632/oncotarget.12512.

2. Baird Jason R., Zipeng Feng, Hong D. Xiao, David Friedman, Ben Cottam, Bernard A. Fox, Gwen Kramer, Rom S. Leidne STING expression and response to treatment with STING ligands in premalignant and malignant disease. PLOS one. 2017, pp.1-16 https://doi.org/10.1371/journal.pone.0187532

3. Baldwin Susan L, Tim D Powell, Karen Sellins, Michael Milhausen The biological effects of five feline IFN-α subtypes. Vet. Immunol. Immunopathol., 2004, Vol. 99, pp.153-67 DOI10.1016/j.vetimm.2004.01.012

4. Boesch A., Cattori V., Riond B., Willi B., Meli M.L., Rentsch K.R., Hosie M.J., Hofmann-Lehmann R., Lutz H. Evaluation of the effect of short-term treatment with the integrase inhibitor raltegravir (Isentress™) on the course of progressive feline leukemia virus infection. Vet. Microbiol., 2015, Vol. 175,pp.167-178

5. Brosh R. and V. Rotter, “When mutants gain new powers: news from the mutant p53 field. Nat. Rev. Cancer., 2009. Vol. 9, pp. 701–713. DOI: 10.1038/nrc2693

6. Cummins JM, Tompkins MB, Olsen R, Tompkins WA, Lewis MG Oral use of human alpha interferon in cats. J Biol Response Mod., 1988. Vol. 7, pp.513–523 PMID:3183686

7. de Mari K, Maynard L, Sanquer A, Lebreux B, Eun HM. Therapeutic effects of recombinant feline interferon-omega on feline leukemia virus (FeLV)-infected and FeLV/feline immunodeficiency virus (FIV)-coinfected symptomatic cats. J. Vet. Intern. Med., 2004, Vol. 18, pp.477-82.

8. De Noronha F., Grant C. K., Lutz H., Keyes A., Rouston W. Circulating levelsof feline leukemia and sarcoma viruses and fibrosarcoma regression in persistently viremic cats. CancerResearch, 1983, Vol. 43, pp.1663-1668

9. Donnelly Raymond P., Harold Dickensheets, Thomas R.O’Brien Interferon-lambda and therapy for chronic hepatitis C virus infection. Trends Immunol., 2011, Volume 32, ] pp. 443-450 https://doi.org/10.1016/j.it.2011.07.002Get rights and content

10. Feline Leukemia Virus and Related Diseases in Cats – Overview”. Generalized Conditions - Veterinary Manual. By Levy J. K. and Burling A. 2018. P.1-9. https://www.msdvetmanual.com/generalized-conditions/feline-leukemia-virus-and-related-diseases/feline-leukemia-virus-and-related-diseases-in-cats-overview#v12847550

11. Fiorito F, Cantiello A, Granato GE, Navas L, Diffidenti C, De Martino L, Maharajan V, Olivieri F, Pagnini U, Iovane G. Clinical improvement in feline herpesvirus 1 infected cats by oral low dose of interleukin-12 plus interferon-gamma. Comp. Immunol. Microbiol Infect Dis., 2016, Vol. 48, pp.41-7. doi: 10.1016/j.cimid.2016.07.006

12. Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, Zaretsky JM, Sun L, Hugo W, Wang X, Parisi G, Saus CP, Torrejon DY, Graeber TG, Comin-Anduix B, Hu-Lieskovan S, Damoiseaux R, Lo RS, Ribas A. Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell Rep., 2017, Vol. 9, pp.1189-1201. doi: 10.1016/j.celrep.2017.04.031.

13. Gil S., R.O.Leal, D.McGahie, N.Sepúlveda, A.Duarte, M.M.R.E.Niza, L.Tavares “Oral Recombinant Feline Interferon-Omega as an alternative immune modulation therapy in FIV positive cats: Clinical and laboratory evaluation”. Research Vet. Sci., 2014. Vol. 96, pp. 79-85 https://doi.org/10.1016/j.rvsc.2013.11.007

14. Grant C. K., De Noronha F., Tusch C., Michalek M. T., McLane M. F. Protection of cats against progressive firbrosarcoma and persistent leukemia virus infection by vaccination with feline leukemia cells. Journal of the National Cancer Institute. 1980. Vol.65, pp.1285-1292

15. Hartmann K. "Chapter 11: Feline leukemia virus infection". In Greene, Craig E. Infectious diseases of the dog and cat (4 ed.). Elsevier Health Sciences. 2013. ISBN 9780323266215.

16. Hartmann K. Efficacy of antiviral chemotherapy for retrovirus-infected cats. What does the current literature tell us?. J. Fel. Med. Surg., 2015. Vol. 17, pp. 925–939 doi: 10.1177/1098612X15610676

17. Hardy W. D., McClelland A. J. Feline leukemia virus: its related diseases and control. Vet. Clin. North Am., 1977. Vol. 7, pp. 93-103.

18. Helfer-Hungerbuehlera A. K., Widmera S., Kesslera Y., Rionda B., Borettib F. S., Grestc P., Lutza H., Hofmann-Lehmanna R. Long-term follow up of feline leukemia virus infection and characterization of viral RNA loads using molecular methods in tissues of cats with different infection outcomes. Virus Res.,2015, Vol. 197, Pages 137–150

19. Hideyuki Ishiguro, Masahiro Kimura, Hiroki Takahashi, Tatsuya Tanaka, Koji Mizoguchi, Hiromitsu Takeyama GADD45A expression is correlated with patient prognosis in esophageal cancer. Oncol Lett., 2016. Vol. 11, pp.277–282. doi: 10.3892/ol.2015.3882

20. Hoffman B, Liebermann DA. Gadd45 in modulation of solid tumors and leukemia». Adv Exp Med Biol., 2013, Vol. 793, pp. 21-33. doi: 10.1007/978-1-4614-8289-5_2.

21. Huang Wen-Shih, Yi-Hung Kuo, Hsing-Chun Kuo, Meng-Chiao Hsieh, Cheng-Yi Huang, Ko-Chao Lee, Kam-Fai Lee, Chien-Heng Shen, Shui-Yi Tung, Chih-Chuan Teng CIL-102-Induced Cell Cycle Arrest and Apoptosis in Colorectal Cancer Cells via Upregulation of p21 and GADD45. PLOS one, 2017. https://doi.org/10.1371/journal.pone.0168989

22. Jarrett O. Pathogenicity of feline leukemia virus is commonly associated with variant viruses. Leukemia, 1992. Vol.6, № 3, P.153-154

23. Jas D., Soyer C., De Fornel-Thibaud P., Oberli F., Vernes D., Guigal P.M., Poulet H., Devauchelle P. Adjuvant immunotherapy of feline injection-site sarcomas with the recombinant canarypox virus expressing feline interleukine-2 evaluated in a controlled monocentric clinical trial when used in association with surgery and brachytherapy. Trials in Vaccinol., 2015. Vol.4, pp. 1–8 http://dx.doi.org/10.1016/j.trivac.2014.11.001

24. Kelm Noah E., Ziwen Zhu, Vivi A. Ding, Huaping Xiao, Mark R. Wakefield, Qian Bai, Yujiang Fang "The role of IL-29 in immunity and cancer. Crit.Rev. Oncol./Hematol. 2016. Vol. 106, pp. 91-98 doi: 10.1016/j.critrevonc.2016.08.002

25. Klotz D., Baumgärtner W., Gerhauser I.Type I interferons in the pathogenesis and treatment of canine diseases(Review). Vet.Immunol. Immunopathol. 2017. Vol. 191, pp. 80-93. DOI: 10.1016/j.vetimm.2017.08.006

26. Kociba G. J., C. Garg, N. M. Khan, A. Reiter, C. Chatfield Effects of orally administered interferon-α on the pathogenesis of feline leukaemia virus-induced erythroid aplasia. Comp. Haematol. Intern. 1995, Vol. 5, pp.79–83

27. Koníková E, Kusenda J. Altered expression of p53 and MDM2 proteins in hematological malignancies. Neoplasma. 2003; Vol.50, pp.31-40. PMID: 12687276

28. Lasfa Ahmed, Andrew Zloza, Karine A. Cohen-Solal IFN-lambda therapy: current status and future perspectives. Drug Discovery Today, 2016, Vol. 21, pp.167-171. https://doi.org/10.1016/j.drudis.2015.10.021

29. Lazear Helen M, Timothy J.Nice, Michael S.Diamond«Interferon-λ: Immune Functions at Barrier Surfaces and Beyond. Immunity Review., 2015, Volume 43, pp. 15-28 https://doi.org/10.1016/j.immuni.2015.07.001

30. Li S.-F., Zhao F.-R., Shao J.-J., Xie Y.-L., Chang H.-Y., Zhang Y.-G.Interferon-omega: Current status in clinical applications(Review). International Immunopharmacology. 2017. Vol. 52, pp. 253-260

31. Louwerens M., London C.A., Pedersen N.C., Lyons L.A. Feline lymphoma in the post-feline leukemia virus era". Journal of veterinary internal medicine. 2005, Vol. 19, pp.329–35. doi:10.1111/j.1939-1676.2005.tb02703.x

32. Magimaidas Andrew, Priyanka Madireddi, Silvia Maifrede, Kaushiki Mukherjee, Barbara Hoffman, Dan A. Liebermann Gadd45b deficiency promotes premature senescence and skin aging. Oncotarget., 2016. Vol. 7, pp.26935-26948

33. McCarty, J. M., Grant, C. K. Feline cytotoxic immune mechanisms against virus-associated leukemia and fibrosarcoma. Cel. Immunol., 1983. Vol. 81, pp.157-168.

34. Mentlik James, A.; Cohen, A.D.; Campbell, K.S. Combination immune therapies to enhance anti-tumor responses by NK cells. Front. Immunol., 2013, Vol. 4. doi:10.3389/fimmu.2013.00481.

35. Milićević Zorka, Vladan Bajić, Lada Živković, Jelena Kasapović, Uroš Andjelković, Biljana Spremo-Potparević Identification of p53 and Its Isoforms in Human Breast Carcinoma Cells. Scientific World Journal., 2014. Vol. 2014, pp.1-10. http://dx.doi.org/10.1155/2014/618698

36. Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev., 2013, Vol. 18. doi: 10.1002/14651858.CD008955.pub2.

37. Moore G.E., DeSantis-Kerr A.C., Guptill L.F., Glickman N.W., Lewis H.B., Lawrence T. Adverse events after vaccine administration in cats: 2,560 cases (2002–2005). Glickman. J. Am. Vet.Med. Assoc. 2007, Vol. 231, pp. 94-100 https://doi.org/10.2460/javma.231.1.94

38. Mukherjee Kaushiki, Xiaojin Sha, Ravi Bhatia, Barbara Hoffman and Dan Liebermann Loss of Stress Sensor GADD45a Accelerates BCR-ABL-Driven Leukemogenesis. Blood, 2011, Vol. 118, pp.1668. doi: 10.18632/oncotarget.14580

39. Namikawa K., Tsutsumida A., Mizutani T., Tsuchida T., Yamazaki N. Randomized phase III trial of adjuvant therapy with locoregional interferon beta versus surgery alone in stage II/III cutaneous melanoma. Japan Clinical Oncology Group Study (JCOG1309, J-FERON). Jpn. J. Clin. Oncol., 2017. Vol. 47, pp. 664-667 DOI: 10.1093/jjco/hyx063

40. Oikawa T1, Okuda M, Kaneko N, Watanabe M, Hiraoka H, Itamoto K, Nakaichi M, Mizuno T, Inokuma H. Cloning of the feline GADD45 cDNA and analysis of its mutation in feline lymphoma cell lines. J. Vet Med Sci., 2006, Vol.68, pp.297-301

41. Okuda M, Umeda A, Sakai T, Ohashi T, Momoi Y, Youn HY, Watari T, Goitsuka R, Tsujimoto H, Hasegawa A. Cloning of feline p53 tumor-suppressor gene and its aberration in hematopoietic tumors. Int. J. Cancer, 1994, Vol. 58, pp.602-7.

42. Oren M. and V. Rotter, Mutant p53 gain-of-function in cancer. Cold Spring Harbor Perspect. Biol., 2010. Vol. 2, pp. 1-16.

43. Osterhaus A., Weijer K., Uytdehaag F., Knell P., Jarrett O., Akerblom L., Morein B. Serological responses in cats vaccinated with FeLV ISCOM and an inactivated FeLV vaccine. Vaccine, 1989. Vol. 7, pp.137-141

44. Patel M., Carritt K., Lane J., Jayappa H., Stahl M., Bourgeoisb M. Comparative Efficacy of Feline Leukemia Virus (FeLV) Inactivated Whole-Virus Vaccine and Canarypox Virus-Vectored Vaccine during Virulent FeLV Challenge and Immunosuppression. Clinical and Vaccine Immunology, 2015, Vol. 22, pp.798-805 doi:10.1128/CVI.00034-15

45. Peller S., Rotter, V. TP53 in hematological cancer: Low incidence of mutations with significant clinical relevance. Human Mutation., 2003, Vol.21, pp. 277-284. doi: 10.1002/humu.10190

46. Poulet H., Brunet S., Boularand C., Guiot A.L., Leroy V., Tartaglia J., Minke J., Audonnet J.C., Desmettre P. Efficacy of a canarypox virus-vectored vaccine against feline leukaemia. Vet. Rec., 2003, Vol.153, pp. 141–145. doi:10.1136/vr.153.5.141

47. Quanhai Li, Kiyoko Kawamura, Guangyu, Ma FumiIwata, Muneo Numasaki, Nobuo Suzuki, Hideaki Shimada, Masatoshi Tagawa «nterferon-λ induces G1 phase arrest or apoptosis in oesophageal carcinoma cells and produces anti-tumour effects in combination with anti-cancer agents. Eur. J. Cancer. 2010, Vol. 46, pp.180-190. https://doi.org/10.1016/j.ejca.2009.10.002Get rights and content

48. Regan Daniel and Dow Steven Manipulation of Innate Immunity for Cancer Therapy in Dogs. Vet. Sci., 2015, Vol.2, pp.423-439. doi:10.3390/vetsci2040423

49. Richards J., Elston T., Ford R., Gaskell R., Hartmann K., Hurley K., Lappin M., Levy J., Rodan I., Scherk M., Schultz R., Sparkes A. The development of sarcomas with the use of the old FeLV and other vaccines may be due to the inflammation caused by aluminium adjuvants in the vaccines: The 2006 American Association of Feline Practitioners Feline Vaccine Advisory Panel report. J. Am. Vet. Med. Assoc., 2006, Vol. 229, pp.1405–41. doi:10.2460/javma.229.9.1405

50. Robert-Tissota Céline, Rüeggera Vera L. Cattoria Valentino, Melia Marina L., Rionda Barbara, Alice Gomes-Kellera Maria, Vögtlinb Andrea, Wittigc Burghardt, Juhlsc Christiane, Hofmann-Lehmanna Regina, Lutza Hans "The innate antiviral immune system of the cat: Molecular tools for the measurement of its state of activation". Vet. Immunol. Immunopathol., 2011. Vol. 143, pp. 269– 281. doi:10.1016/j.vetimm.2011.06.005

51. Rodolfo Oliveira Leal, Solange Gil, Maria TV Brito, David McGahie, Maria MRE Niza, Luís Tavares “The use of oral recombinant feline interferon omega in two cats with type II diabetes mellitus and concurrent feline chronic gingivostomatitis syndrome”. Ir. Vet J. 2013; Vol. 66(1): pp. 19. doi: 10.1186/2046-0481-66-19

52. Rovnak J. and Quackenbush S.L. “Walleye Dermal Sarcoma Virus: Molecular Biology and Oncogenesis”. Viruses, 2010, Vol. 2,pp.1984–1999. doi: 10.3390/v2091984

53. Sellmann L., Carpinteiro A., Nückel H., Scholtysik R., Siemer D., Klein-Hipass L., Kube D., Dürig, J., Dührsen U., Stanelle J., Küppers R. p53 protein expression in chronic lymphocytic leukemia”. Leukemia and Lymphoma, 2012.Vol. 53, pp. 1282-1288. DOI: 10.3109/10428194.2011.654115

54. Shin DL, Hatesuer B, Bergmann S, Nedelko T, Schughart K. Protection from Severe Influenza Virus Infections in Mice Carrying the Mx1 Influenza Virus Resistance Gene Strongly Depends on Genetic Background. J. Virol., 2015, Vol. 89, pp.9998-10009. doi: 10.1128/JVI.01305-15

55. Staeheli P, Grob R, Meier E, Sutcliffe JG, Haller O. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Mol Cell Biol., 1988, Vol.8, pp.4518-23. PMCID: PMC365527

56. Stuetzer Bianca, Konstanze Brunner, Hans Lutz, Katrin Hartmann A trial with 3′-azido-2′,3′-dideoxythymidine and human interferon-α in cats naturally infected with feline leukaemia virus. Journal of Feline Medicine and Surgery, 2013,Vol. 15, pp. 667–671

57. Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF. “GADD45 proteins: central players in tumorigenesis”. Curr. Mol. Med., 2012, Vol.12, pp.634-51.

58. Umberto Cardellino, Yari Ciribilli, Virginia Andreotti, Paola Modesto, Paola Menichini, Gilberto Fronza, Claudio Pellegrino, Alberto Inga Transcriptional properties of feline p53 and its tumour-associated mutants: a yeast-based approach. Mutagenesis, 2007.Vol. 22, pp. 417–423. https://doi.org/10.1093/mutage/gem038

59. Wardley R.C., Berlinski P.J., Thomsen D.R., Meyer A.L., Post L.E. The use of feline herpesvirus and baculovirus as vaccine vectors for the gag and e n v genes of feline leukaemia virus. J.G. Virol., 1992, Vol.73, p.1811-1818.

60. Yasuhiro Tezuka, Shunsuke Endo, Aya Matsui, Atsuko Sato, Katsuyo Saito, Kentaro Semba, Masafumi Takahashi, Takashi Murakami «Potential anti-tumor effect of IFN-λ2 (IL-28A) against human lung cancer cells». Lung Cancer, 2012, Vol. 78, 2012, pp. 185-192 https://doi.org/10.1016/j.lungcan.2012.09.005

61. Zhang L, Yang Z, Ma A, Qu Y, Xia S, Xu D, Ge C, Qiu B, Xia Q, Li J, Liu Y . Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma. Hepatol., 2014, Vol.59, pp.178–89. doi:10.1002/hep.26628.

62. Zhao H., Ma J., Wang Y., Liu J., Shao Y., Li J., Jiang G.Molecular cloning and functional characterization of eleven subtypes of interferon-α in Amur tigers (Panthera tigris altaica). Dev. Comp. Immunol. 2017,Vol. 77, pp.46-55