jofinЖурнал инфектологииJournal Infectology2072-6732IPO “АIDSSPbR"10.22625/2072-6732-2017-9-1-31-39jofin-558Research ArticleОбзорReviewГЕННАЯ КЛЕТОЧНАЯ ТЕРАПИЯ ВИЧ И ЗЛОКАЧЕСТВЕННЫХ ОПУХОЛЕЙ КРОВЕТВОРНОЙ И ЛИМФАТИЧЕСКОЙ ТКАНИ НА ОСНОВЕ ТРАНСПЛАНТАЦИИ ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК С ИСПОЛЬЗОВАНИЕМ САЙТ-СПЕЦИФИЧЕСКОГО РЕДАКТИРОВАНИЯ ГЕНОМАGENE-CELL THERAPY OF HIV AND HEMATOLOGICAL MALIGNANCES BASED ON HEMATOPOIETIC STEM CELL TRANSPLANTATION AND SITE-SPECIFIC GENOME EDITINGПоповаМ. О.PopovaM. О.

Saint-Petersburg

marina.popova.spb@gmail.comСергеевВ. С.SergeevV. S.

Saint-Petersburg

sergeev.vlad@gmail.comЛепикК. В.LepikK V.

Лепик Кирилл Викторович – врач-гематолог

Saint-Petersburg

lepikkv@gmail.comШакироваА. И.ShakirovaA. I.

Saint-Petersburg

lilyup@yandex.ruПоттерА. Я.PotterA. Ya.

Saint-Petersburg

potteralisa@gmail.comБархатовИ. М.BarhatovI. M.

Saint-Petersburg

i.barkhatov@gmail.comФезеБ.FehseB.

Research Department Cell and Gene Therapy, Dept. of Stem Cell Transplantation 

Hamburg

АфанасьевБ. В.AfanasyevB. V.

Saint-Petersburg

bmt-director@spb-gmu.ruНаучно-исследовательский институт детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. академика И.П. ПавловаРоссияScience Research Institute of Children’s Oncology, Hematology and Transplantation named after R.M. Gorbacheva of First Saint-Petersburg State Medical University named after academician I.P. PavlovRussian FederationМедицинский центр университета Гамбург-ЭппендорфГерманияUniversity Medical Center (UKE) Hamburg-EppendorGermany201705042017913139Copyright © Попова М.О., Сергеев В.С., Лепик К.В., Шакирова А.И., Поттер А.Я., Бархатов И.М., Фезе Б., Афанасьев Б.В., 20172017Попова М.О., Сергеев В.С., Лепик К.В., Шакирова А.И., Поттер А.Я., Бархатов И.М., Фезе Б., Афанасьев Б.В.Popova M.О., Sergeev V.S., Lepik K.V., Shakirova A.I., Potter A.Y., Barhatov I.M., Fehse B., Afanasyev B.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.niidi.ru/jofin/article/view/558

По данным ежегодных докладов UNAIDS, c1983 г. количество ВИЧ-инфицированных пациентов неуклонно растет. Антиретровирусная терапия (АРВТ) позволяет увеличить продолжительность жизни, но проблемы качества жизни и долгосрочной выживаемости не решены. Одной из основных причин летальности у пациентов с ВИЧ в эру АРВТ являются онкологические заболевания, среди которых значительную часть составляют злокачественные лимфомы. Лечение лимфом включает этапную противоопухолевую химиотерапию (ПХТ) с потенциалом полного излечения пациента. Высокодозная ПХТ с аутологичной трансплантацией гемопоэтических стволовых клеток (ТГСК) – основное средство лечения рецидивов и рефрактерных форм агрессивных злокачественных лимфом. В последние годы с появлением технологии редактирования генома аутологичная ТГСК становится также одним из самых перспективных методов лечения ВИЧ-инфекции. История излечения от ВИЧ «Берлинского пациента» благодаря аллогенной ТГСК от донора с мутацией гена CCR5 продемонстрировала эффективность подхода генной терапии на основе трансплантации. Высокодозная химиотерапия с трансплантацией аутологичных, подвергнутых редактированию (инактивации гена CCR5, с помощью генно-инженерных нуклеаз), гемопоэтических стволовых клеток потенциально представляет собой способ комплексного лечения этих пациентов. С одной стороны, высокодозная ПХТ с ауто-ТГСК обеспечивает излечение от злокачественной опухоли, с другой стороны, она является способом доставки отредактированных клеток и создания условий для реализации лечебного эффекта против ВИЧ.

Данный обзор посвящён методам лечения опухолей кроветворной и лимфатической ткани и ВИЧинфекции с использованием редактирования генома на основе трансплантации гемопоэтических стволовых клеток. 

Based on the annual UNAIDS reports the number of HIVinfected patients is continually growing since 1983. Antiretroviral Therapy (ART) allows to prolong life expectancy, but the problem of life quality and overall survival is still remaining. Nowadays, in the era of ART, one of the main cause of mortality in HIV-infected patients is malignancies. Lymphomas play one of the key roles in this group of diseases. The treatment of lymphomas includes combined regiments of chemotherapy with a curative potential. High dose chemotherapy with autologous hematopoietic stem cell transplant (auto-HSCT) is the main path of the treatment for relapsed / refractory lymphomas. In the last few years with a development of the genome editing technology auto-HSCT is becoming one of the most promising methods of HIV treatment. The case of “Berlin patient” when allogeneic HSCT from donor with mutation CCR5-delta32 lead to cure from HIV and proof of concept the efficacy of the gene therapy for HIV based on HSCT. Hematopoietic stem cell transplantation with edited autologous HSC (CCR5 knockout by site-specific genome editing tools with engineering nucleases) is a comprehensive treatment for this cohort of patients. On one hand, high dose chemotherapy with auto-HSCT cures the malignancy; on the other hand auto-HSCT works as a delivery method for the edited cells and creates an environment for the HIV eradication. This review is dedicated to HIV and oncology, methods of treatment of hematological malignancies and HIV-infection using genome editing technology based on HSCT.

ВИЧгенная клеточная терапияCCR5редактирование геномаZFNTALENCRISPR/ Cas9HIVgene cell therapyCCR5genome editingZFNTALENCRISPR/Cas9Referenceshttp://aidsinfo.unaids.org/http://aidsinfo.unaids.org/Информационный бюллетень №40 Федерального научно-методического Центра по профилактике и борьбе со СПИДом. – М., 2015. – http://www.hivrussia.org/files/bul_40.pdf)Informacionnyj bjulleten’ №40 Federal’nogo nauchnometodicheskogo Centra po profilaktike i bor’be so SPIDom. Moskva 2015 (http://www.hivrussia.org/files/bul_40.pdf).Grulich A. E., van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370(9581):59–67. DOI: http://dx.doi.org/10.1016/S0140-6736(07)61050-2.Grulich A. E., van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370(9581):59–67. DOI: http://dx.doi.org/10.1016/S0140-6736(07)61050-2.Engels E.A., Pfeiffer R.M., Goedert J.J., et al. HIV/AIDS Cancer Match Study. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS.2006;20:1645–54. doi: 10.1097/01.aids.0000238411.75324.59Engels E.A., Pfeiffer R.M., Goedert J.J., et al. HIV/AIDS Cancer Match Study. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS.2006;20:1645–54. doi: 10.1097/01.aids.0000238411.75324.59Shiels M., Pfeiffer R., Gail M., et al. Cancer Burden in the HIV-Infected Population in the United States. J Natl Cancer Inst 2011;103:753–762. DOI: 10.1093/jnci/djr076.Shiels M., Pfeiffer R., Gail M., et al. Cancer Burden in the HIV-Infected Population in the United States. J Natl Cancer Inst 2011;103:753–762. DOI: 10.1093/jnci/djr076.Oriol A, Ribera JM, Bergua J, et al. High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma: comparison of results in human immunodeficiency virus-infected and noninfected patients. Cancer. 2008;113(1):117-125.Oriol A, Ribera JM, Bergua J, et al. High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma: comparison of results in human immunodeficiency virus-infected and noninfected patients. Cancer. 2008;113(1):117-125.Montoto S., Shaw K., Okosun J., et al. HIV Status Does Not Influence Outcome in Patients With Classical Hodgkin Lymphoma Treated With Chemotherapy Using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the Highly Active Antiretroviral Therapy Era. JCO 2012;30:4111-4116. doi: 10.1200/JCO.2012.44.8373.Montoto S., Shaw K., Okosun J., et al. HIV Status Does Not Influence Outcome in Patients With Classical Hodgkin Lymphoma Treated With Chemotherapy Using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the Highly Active Antiretroviral Therapy Era. JCO 2012;30:4111-4116. doi: 10.1200/JCO.2012.44.8373.Passweg JR, Baldomero H, Bader P et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40000 transplants annually. Bone Marrow Transplantation (2016);1-7; doi: 10.1038/bmt.2016.20.Passweg JR, Baldomero H, Bader P et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40000 transplants annually. Bone Marrow Transplantation (2016);1-7; doi: 10.1038/bmt.2016.20.Krishnan A, Molina A, Zaia J, et al. Durable remissions with autologous stem cell transplantation for high-risk HIVassociated lymphomas. Blood. 2005;105:874–878. DOI: http://dx.doi.org/10.1182/blood-2004-04-1532.Krishnan A, Molina A, Zaia J, et al. Durable remissions with autologous stem cell transplantation for high-risk HIVassociated lymphomas. Blood. 2005;105:874–878. DOI: http://dx.doi.org/10.1182/blood-2004-04-1532.Balsalobre P, Díez-Martín JL, Re A, et al. Autologous stem-cell transplantation in patients with HIV-related lymphoma. J Clin Oncol. 2009;27(13):2192–2198.Balsalobre P, D ez-Mart n JL, Re A, et al. Autologous stem-cell transplantation in patients with HIV-related lymphoma. J Clin Oncol. 2009;27(13):2192–2198.Re A, Michieli M, Casari S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors. Blood. 2009;114:1306–1313. DOI: http://dx.doi.org/10.1182/blood-2009-02-202762.Re A, Michieli M, Casari S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors. Blood. 2009;114:1306–1313. DOI: http://dx.doi.org/10.1182/blood-2009-02-202762.Diez-Martin JL, Balsalobre P, Re A, et al. Comparable survival between HIV+ and HIV– non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation. Blood. 2009;113(23):6011–6014. DOI: http://dx.doi.org/10.1182/blood-2008-12-195388.Diez-Martin JL, Balsalobre P, Re A, et al. Comparable survival between HIV+ and HIV– non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation. Blood. 2009;113(23):6011–6014. DOI: http://dx.doi.org/10.1182/blood-2008-12-195388.Krishnan A, Palmer JM, Zaia JA, et al. HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Biol Blood Marrow Transplant. 2010;16(9):1302–1308. DOI: http://dx.doi.org/10.1016/j.bbmt.2010.03.019.Krishnan A, Palmer JM, Zaia JA, et al. HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Biol Blood Marrow Transplant. 2010;16(9):1302–1308. DOI: http://dx.doi.org/10.1016/j.bbmt.2010.03.019.Serrano D, Miralles P, Balsalobre P, et al. Graft-VersusTumor Effect After Allogeneic Stem Cell Transplantation in HIV-Positive Patients With High-Risk Hematologic Malignancies. AIDS RESEARCH AND HUMAN RETROVIRUSES 2013; Vol 29, N10: 1340-5. DOI: 10.1089/aid.2013.0001.Serrano D, Miralles P, Balsalobre P, et al. Graft-VersusTumor Effect After Allogeneic Stem Cell Transplantation in HIV-Positive Patients With High-Risk Hematologic Malignancies. AIDS RESEARCH AND HUMAN RETROVIRUSES 2013; Vol 29, N10: 1340-5. DOI: 10.1089/aid.2013.0001.Afanasyev B., Popova M., Bondarenko S., et al. SaintPetersburg experience of allogeneic hematopoietic stem cell transplantation in patients with acute leukemia and human immunodeficiency virus. Cellular Therapy and Transplantation (CTT). Vol.4, No.1-2, 2015. doi: 10.18620/1866-8836-2015-4-12-24-30.Afanasyev B., Popova M., Bondarenko S., et al. SaintPetersburg experience of allogeneic hematopoietic stem cell transplantation in patients with acute leukemia and human immunodeficiency virus. Cellular Therapy and Transplantation (CTT). Vol.4, No.1-2, 2015. doi: 10.18620/1866-8836-2015-4-12-24-30.Hütter G. and Zaia J. A. Allogeneic haematopoietic stem cell transplantation in patients with human immunodeficiency virus: the experiences of more than 25 years. Clinical and Experimental Immunology, 163: 284–295. doi:10.1111/j.13652249.2010.04312.x.Hütter G. and Zaia J. A. Allogeneic haematopoietic stem cell transplantation in patients with human immunodeficiency virus: the experiences of more than 25 years. Clinical and Experimental Immunology, 163: 284–295. doi:10.1111/j.13652249.2010.04312.x.Kang EM, de Witte M, Malech H et al. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood 2002; 99:698–701.Kang EM, de Witte M, Malech H et al. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood 2002; 99:698–701.Liu R, Paxton WA, Choe S., et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply exposed individuals to HIV-1 infection. Cell 1996; 86: 367– 377.Liu R, Paxton WA, Choe S., et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply exposed individuals to HIV-1 infection. Cell 1996; 86: 367– 377.Кофиади, И.А. Генетическая устойчивость к заражению ВИЧ и развитию СПИД в популяциях России и сопредельных государств : автореф. дисс. … канд. биолог. наук / И.А. Кофиади. – М., 2008.Kofiadi I.A. Geneticheskaja ustojchivost’ k zarazheniju VICh i razvitiju SPID v populjacijah Rossii i sopredel’nyh gosudarstv. Avtoreferat dissertacii na soiskanie uchenoj stepeni kandidata biologicheskih nauk, 16 APR 2008, Moskva.Burnett JC, Li H., et al. Progress toward curing HIV infection with hematopoietic cell transplantation. Stem Cells Cloning. 2015 Jul 28;8:109-16. doi: 10.2147/SCCAA.S56050.Burnett JC, Li H., et al. Progress toward curing HIV infection with hematopoietic cell transplantation. Stem Cells Cloning. 2015 Jul 28;8:109-16. doi: 10.2147/SCCAA.S56050.Marrow Transplants Fail to Cure Two H.I.V. Patients. New York Times Dec. 6, 2013 by Donald G. McNeil Jr.. (http://www.nytimes.com).Marrow Transplants Fail to Cure Two H.I.V. Patients. New York Times Dec. 6, 2013 by Donald G. McNeil Jr.. (http://www.nytimes.com).Urnov F.D., Rebar E.J., Holmes M.C., et al. Genome editing with engineered zinc finger nucleases. Nat Rev Genet (2010) 11(9):636–46. 10.1038/nrg2842Urnov F.D., Rebar E.J., Holmes M.C., et al. Genome editing with engineered zinc finger nucleases. Nat Rev Genet (2010) 11(9):636–46. 10.1038/nrg2842Perez EE, Wang J, Miller JC, et al. Establishment of HIV1 resistance in CD4+T cells by genome editing using zinc-finger nucleases. Nature biotechnology. 2008;26(7):808-816.Perez EE, Wang J, Miller JC, et al. Establishment of HIV1 resistance in CD4+T cells by genome editing using zinc-finger nucleases. Nature biotechnology. 2008;26(7):808-816.Holt N, Wang J, Kim K, et al. Zinc finger nuclease-mediated CCR5 knockout hematopoietic stem cell transplantation controls HIV-1 in vivo. Nat Biotechnol (2010) 28(8):839– 47. 10.1038/nbt.1663.Holt N, Wang J, Kim K, et al. Zinc finger nuclease-mediated CCR5 knockout hematopoietic stem cell transplantation controls HIV-1 in vivo. Nat Biotechnol (2010) 28(8):839– 47. 10.1038/nbt.1663.Tebas P, Stein D, Tang W, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370: 901–10. doi: 10.1056/NEJMoa1300662 (https://clinicaltrials.gov/ct2/show/record/NCT01044654).Tebas P, Stein D, Tang W, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370: 901–10. doi: 10.1056/NEJMoa1300662 (https://clinicaltrials.gov/ct2/show/record/NCT01044654).Mock U., Machowicz R., Hauber I., et al. mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5. Nucl. Acids Res. first published online May 11, 2015 doi:10.1093/nar/gkv469.Mock U., Machowicz R., Hauber I., et al. mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5. Nucl. Acids Res. first published online May 11, 2015 doi:10.1093/nar/gkv469.Mock U., Hauber I., Fehse B. Digital PCR to assess geneediting frequencies (GEF-dPCR) mediated by designer nucleases. Nat Protoc. 2016;11(3):598-615.Mock U., Hauber I., Fehse B. Digital PCR to assess geneediting frequencies (GEF-dPCR) mediated by designer nucleases. Nat Protoc. 2016;11(3):598-615.Shi, B., Li, J., Shi, X., et al. TALEN-mediated knockout of CCR5 confers protection against infection of human immunodeficiency virus. JAIDS Journal of Acquired Immune Deficiency Syndromes: Post Acceptance: October 03, 2016. doi: 10.1097/QAI.0000000000001190.Shi, B., Li, J., Shi, X., et al. TALEN-mediated knockout of CCR5 confers protection against infection of human immunodeficiency virus. JAIDS Journal of Acquired Immune Deficiency Syndromes: Post Acceptance: October 03, 2016. doi: 10.1097/QAI.0000000000001190.Mandal PK, Ferreira LM, Collins R, et al. Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9. Cell Stem Cell. 2014;15(5):643–52. 10.1016/j.stem.2014.10.004.Mandal PK, Ferreira LM, Collins R, et al. Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9. Cell Stem Cell. 2014;15(5):643–52. 10.1016/j.stem.2014.10.004.Ebina H., Misawa N., Kanemura Y. et al. Harnessing the CRISPR/Cas9 System to Disrupt Latent HIV-1 Provirus. Scientific Reports 3 (August 26, 2013), doi:10.1038/srep02510.Ebina H., Misawa N., Kanemura Y. et al. Harnessing the CRISPR/Cas9 System to Disrupt Latent HIV-1 Provirus. Scientific Reports 3 (August 26, 2013), doi:10.1038/srep02510.Kaminski R., Chen Y., Fischer T., et al. Elimination of HIV-1 Genomes from Human T-lymphoid Cells by CRISPR/ Cas9 Gene Editing. Scientific Reports 6, Article number: 22555 (2016). doi:10.1038/srep22555.Kaminski R., Chen Y., Fischer T., et al. Elimination of HIV-1 Genomes from Human T-lymphoid Cells by CRISPR/ Cas9 Gene Editing. Scientific Reports 6, Article number: 22555 (2016). doi:10.1038/srep22555.De Silva Feelixge H.S., Stonea D., Pietz H.L., et al. Detection of treatment-resistant infectious HIV after genome-directed antiviral endonuclease therapy. Antiviral Research, Vol 126, Feb 2016, P 90–98. doi:10.1016/j.antiviral.2015.12.007.De Silva Feelixge H.S., Stonea D., Pietz H.L., et al. Detection of treatment-resistant infectious HIV after genome-directed antiviral endonuclease therapy. Antiviral Research, Vol 126, Feb 2016, P 90–98. doi:10.1016/j.antiviral.2015.12.007.Wang Z., Pan Q., Gendron P., et al. CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape. Cell Reports 15, Issue 3, p481–489, 19 April 2016. DOI: http://dx.doi.org/10.1016/j.celrep.2016.03.042.Wang Z., Pan Q., Gendron P., et al. CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape. Cell Reports 15, Issue 3, p481–489, 19 April 2016. DOI: http://dx.doi.org/10.1016/j.celrep.2016.03.042.Hou P, Chen S, Wang S, et al. Genome editing of CXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection. Scientific Reports. 2015;5:15577. doi:10.1038/srep15577.Hou P, Chen S, Wang S, et al. Genome editing of CXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection. Scientific Reports. 2015;5:15577. doi:10.1038/srep15577.Lepik K.V., Popova M.O., Shakirova A.I. Site-specific genome editing for hematopoetic stem cells transplantation-based gene therapy approaches. Genes and Cells. 2016;11(2):21-9.Lepik K.V., Popova M.O., Shakirova A.I. Site-specific genome editing for hematopoetic stem cells transplantation-based gene therapy approaches. Genes and Cells. 2016;11(2):21-9.

The authors declare that there are no conflicts of interest present.