Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC29910.15690/vramn.v67i5.268INTERNAL DISEASES: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ВНУТРЕННИХ БОЛЕЗНЕЙTREATMENT OF HIV-INFECTION BY MEANS OF GENE THERAPYЛЕЧЕНИЕ ВИЧ-ИНФЕКЦИИ С ПОМОЩЬЮ ГЕННОЙ ТЕРАПИИGlazkovaD. V.ГлазковаД. В.
Russian Federation

кандидат биологических наук, научный сотрудник отдела молекулярной диагностики и эпидемиологии ФБУН ЦНИИ эпидемиологии Роспотребнадзора Адрес: 111123, Москва, ул. Новогиреевская, 3А

glazkova@pcr.ruBogoslovskayaE. V.БогословскаяЕ. В.
Russian Federation

кандидат медицинских наук, старший научный сотрудник отдела молекулярной диагностики и эпидемиологии ФБУН ЦНИИ эпидемиологии Роспотребнадзора Адрес: 111123, Москва, ул. Новогиреевская, д. 3А E-mail: lenabo@pcr.ru Тел./ факс: (495) 305-54-23

lenabo@pcr.ruMarkelovM. L.МаркеловМ. Л.
Russian Federation

кандидат биологических наук, старший научный сотрудник лаборатории постге- номных технологий Института медицины труда РАМН Адрес: 105275, Москва, проспект Буденного, 31

markelov@pcr.ruShipulinG. A.ШипулинГ. А.
Russian Federation

кандидат медицинских наук, заведующий отделом молекулярной диагностики и эпидемиологии ФБУН ЦНИИ эпидемиологии Роспотребнадзора Адрес: 111123, Москва, ул. Новогиреевская, 3А

german@pcr.ruPokrovskiiV. V.ПокровскийВ. В.
Russian Federation

академик РАМН, заместитель директора ФБУН ЦНИИ эпидемиологии Роспотребнадзора по научной работе Адрес: 111123, Москва, ул. Новогиреевская, 3А Тел.: (495) 974-96-46, факс: (495) 305-54-23

info@pcr.ruCentral Research Institute of Epidemiology, Russian Federal service on customers' rights protection and human well-being surveillanceФГБУН «Центральный научно-исследовательский институт эпидемиологии» Роспотребнадзора, МоскваResearch Institute of Occupational Health of Russian Academy of Medical SciencesФГБУ «Институт медицины труда» РАМН, Москва23052012675Вестник Российской академии медицинских наук162307082015Copyright ©; 2012, "Paediatrician" Publishers LLCCopyright ©; 2012, Издательство "Педиатръ"2012"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/299

Current methods of HIV treatment can contain a progression of the disease; however they do not lead to a cure. Lifelong antiretroviral therapy is therefore necessary, leading to problems of cost and toxicity of chemical drugs. The recent advances in science have allowed a new approach to the HIV-treatment — gene therapy. In the present publication we focus on one strategy of the gene therapy called «intracellular immunization». The strategy is based on the introducing of antiviral genes into the HIV-sensitive cells. We highlight the mechanisms of action of various antiviral genetic agents and discuss some issues concerning target cells and genes delivery. Finally we summarize the results of certain gene therapy clinical trials.

Современные методы лечения ВИЧ-инфекции позволяют сдерживать скорость развития заболевания, но не приводят к его излечению. Антиретровирусная терапия является пожизненной, дорогостоящей и сопровождается накоплением побочных эффектов. Последние достижения науки позволили предложить принципиально новый подход к лечению ВИЧ-инфекции — генную терапию. Настоящая публикация посвящена одному из направлений генной терапии ВИЧ, которое получило название «внутриклеточная иммунизация». В основе этого направления лежит идея введения антивирусных генов в чувствительные к ВИЧ клетки. В статье рассмотрены механизмы действия различных антивирусных генетических агентов, обсуждаются вопросы, связанные с выбором клеток-мишеней и способом доставки терапевтических генов. Представлены результаты клинических испытаний некоторых генотерапевтических препаратов для лечения ВИЧ-инфекции.

gene therapyHIVviral vectorantiviral genesгенная терапияВИЧвирусный векторантивирусные гены1. Baltimore D. Gene therapy. Intracellular immunization. Nature. 1988; 335(6189):395–396.2. Engels B, Uckert W. Redirecting T lymphocyte specificity by T cell receptor gene transfer- a new era for immunotherapy. Mol. Aspects Med. 2007; 28(1):115–142.3. Puls R.L., Emery S. Therapeutic vaccination against HIV: current progress and future possibilities. Clin. Sci (Lond). 2006; 110(1):59–71.4. June C.H., Blazar B.R., Riley J.L. Engineering lymphocyte subsets: tools, trials and tribulations. Nat. Rev. Immunol. 2009; 9(10):704–7165. 5.Levine B.L., Humeau L.M., Boyer J. et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc. Natl. Acad. Sci. USA. 2006; 103(46):17372–17377.6. van Lunzen J., Glaunsinger T., Stahmer I. et al. Transfer of autologous gene-modified T cells in HIV-infected patients with advanced immunodeficiency and drug-resistant virus. Mol. Ther. 2007; 15(5):1024–1033.7. Macpherson J.L., Boyd M.P., Arndt A.J. et al. Long-term survival and concomitant gene expression of ribozyme-transduced CD4+ T-lymphocytes in HIV-infected patients. J. Gene Med. 2005; 7(5): 552–564.8. Payne K.J., Crooks G.M. Immune-cell lineage commitment: translation from mice to humans. Immunity. 2007; 26(6): 674–677.9. Kambal A., Mitchell G., Cary W. et al. Generation of HIV-1 resistant and functional macrophages from hematopoietic stem cell-derived induced pluripotent stem cells. Mol. Ther. 2011; 19(3): 584–593.10. Park I.H., Zhao R., West J.A. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008; 451(7175): 141–146.11. Rosenberg S.A., Aebersold P., Cornetta K. et al. Gene transfer into humans — immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N. Engl. J. Med. 1990; 323(9): 570–578.12. Pluta K., Kacprzak M.M. Use of HIV as a gene transfer vector. Acta Biochim. Pol. 2009; 56(4): 531–595.13. Marathe J.G., Wooley D.P. Is gene therapy a good therapeutic approach for HIV-positive patients? Genet. Vaccines Ther. 2007; 5: 5.14. Michienzi A., Li S., Zaia J.A., Rossi J.J. A nucleolar TAR decoy inhibitor of HIV-1 replication. Proc. Natl. Acad. Sci. USA. 2002; 99(22): 14047–14052.15. Mhashilkar A.M., LaVecchio J., Eberhardt B. et al. Inhibition of human immunodeficiency virus type 1 replication in vitro in acutely and persistently infected human CD4+ mononuclear cells expressing murine and humanized anti-human immunodeficiency virus type 1 Tat single-chain variable fragment intrabodies. Hum. Gene Ther. 1999; 10(9): 1453–1467.16. Lamothe B., Joshi S. Current developments and future prospects for HIV gene therapy using interfering RNA-based strategies. Front. Biosci. 2000; 5: 527–555.17. Castanotto D., Li J.R., Michienzi A. et al. Intracellular ribozyme applications. Biochem. Soc. Trans. 2002; 30(Pt. 6): 1140–1145.18. Amado R.G., Mitsuyasu R.T., Rosenblatt J.D. et al. Anti–human immunodeficiency virus hematopoietic progenitor cell–delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1–infected patients. Hum. Gene Ther. 2004; 15: 251–262.19. Lee N.S., Rossi J.J. Control of HIV-1 replication by RNA interference. Virus Res. 2004; 102(1): 53–58.20. ter Brake O., 't Hooft K., Liu Y.P. et al. Lentiviral vector design for multiple shRNA expression and durable HIV-1 inhibition. Mol. Ther. 2008; 16(3): 557–564.21. Aagaard L.A., Zhang J., von Eije K.J. et al. Engineering and optimization of the miR-106b cluster for ectopic expression of multiplexed anti-HIV RNAs. Gene Ther. 2008; 15(23): 1536–1549.22. Lapidot T., Kollet O. The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immunedeficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia. 2002; 16: 1992–2003.23. O'Brien S.J., Moore J.P. The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol. Rev. 2000; 177: 99–111.24. Biti R., French R., Young J. et al. HIV-1 infection in an individual homozygous for the CCR5 deletion allele. Nature Medicine.1997; 3: 252–253.25. Allers K., Hütter G., Hofmann J. et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2011; 117(10): 2791–2799.26. Swan C.H., Torbett B.E. Can gene delivery close the door to HIV-1 entry after escape? J. Med. Primatol. 2006; 35: 236–247.27. Feng Y., Leavitt M., Tritz R. et al. Inhibition of CCR5-dependent HIV-1 infection by hairpin ribozyme gene therapy against CC-chemokine receptor 5. Virology. 2000; 276(2): 271–278.28. Cagnon L., Rossi J.J. Downregulation of the CCR5 beta-chemokine receptor and inhibition of HIV-1 infection by stable VA1-ribozyme chimeric transcripts. Antisense Nucleic Acid Drug Dev. 2000; 10(4): 251–261.29. Swan C.H., Bühler B., Steinberger P. et al. T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery. Gene Ther. 2006; 13(20): 1480–1492.30. Anderson J.S., Javien J., Nolta J.A., Bauer G. Preintegration HIV-1 inhibition by a combination lentiviral vector containing a chimeric TRIM5 alpha protein, a CCR5 shRNA, and a TAR decoy. Mol. Ther. 2009; 17(12): 2103–2114.31. Butticaz C., Ciuffi A., Muñoz M. et al. Protection from HIV-1 infection of primary CD4 T cells by CCR5 silencing is effective for the full spectrum of CCR5 expression. Antivir. Ther. 2003; 8(5): 373–377.32. Kim S.S., Peer D., Kumar P. et al. RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Mol. Ther. 2010; 18(2): 370–376.33. Shimizu S., Hong P., Arumugam B. et al. A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model. Blood. 2010; 115(8): 1534–1544.34. Grimm D., Wang L., Lee J.S. et al. Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver. J. Clin. Invest. 2010; 120(9): 3106–3119.35. Jackson A.L., Linsley P.S. Noise amidst the silence: off-target effects of siRNAs? Trends Genet. 2004; 20(11): 521–524.36. Silva J.M., Li M.Z., Chang K. et al. Second-generation shRNA libraries covering the mouse and human genomes. Nat. Genet. 2005; 37(11): 1281–1288.37. Boden D., Pusch O., Silbermann R. et al. Enhanced gene silencing of HIV-1 specific siRNA using microRNA designed hairpins. Nucleic Acids Res. 2004; 32(3): 1154–1158.38. Liu Y.P., Haasnoot J., ter Brake O. et al. Inhibition of HIV-1 by multiple siRNAs expressed from a single microRNA polycistron. Nucleic Acids Res. 2008; 36(9): 2811–2824.39. Perez E.E., Wang J., Miller J.C. et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat. Biotechnol. 2008; 26(7): 808–816.40. Holt N., Wang J., Kim K. et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat. Biotechnol. 2010; 28(8): 839–847.41. Lalezari J.P., DeJesus E., Northfelt D.W. et al. A controlled phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir. Ther. 2003; 8: 279–287.42. Egelhofer M., Brandenburg G., Martinius H. et al. Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides. J. Virol. 2004; 78: 568–575.43. Strebel K., Luban J., Jeang K.T. Human cellular restriction factors that target HIV-1 replication. BMC Med. 2009; 7: 48.44. Li Y., Li X., Stremlau M. et al. Removal of arginine 332 allows human TRIM5б to bind human immunodeficiency virus capsids and to restrict infection. J. Virol. 2006; 80: 6738–6744.45. Anderson J., Akkina R. Human immunodeficiency virus type 1 restriction by human-rhesus chimeric tripartite motif 5alpha (TRIM 5alpha) in CD34(+) cell-derived macrophages in vitro and in T cells in vivo in severe combined immunodeficient (SCID-hu) mice transplanted with human fetal tissue. Hum. Gene Ther. 2008; 19(3): 217–228.46. Sayah D.M., Sokolskaja E., Berthoux L., Luban J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature. 2004; 430(6999): 569–573.47. Neagu M.R., Ziegler P., Pertel T. et al. Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. J. Clin. Invest. 2009; 119(10): 3035–3047.48. Bogerd H.P., Doehle B.P., Wiegand H.L., Cullen B.R. A single amino acid difference in the host APOBEC3G protein controls the primate species specificity of HIV type 1 virion infectivity factor. Proc. Natl. Acad. Sci. USA. 2004; 101(11): 3770–3774.49. Xu H., Svarovskaia E.S., Barr R. et al. A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion. Proc. Natl. Acad. Sci. USA. 2004; 101(15): 5652–5657.50. Gupta R.K., Hué S., Schaller T. et al. Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion. PLoS Pathog. 2009; 5(5).51. Burdick R., Smith J.L., Chaipan C. et al. P body-associated protein Mov10 inhibits HIV-1 replication at multiple stages. J. Virol. 2010; 84(19): 10241–102453.52. Lee K., Ambrose Z., Martin T.D. et al. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe. 2010; 7(3): 221–233.53. DiGiusto D.L., Krishnan A., Li L. et al. RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma. Sci. Transl. Med. 2010; 2(36).54. Kiem H.P., Wu R.A., Sun G. et al. Foamy combinatorial anti-HIV vectors with MGMTP140K potently inhibit HIV-1 and SHIV replication and mediate selection in vivo. Gene Ther. 2010; 17(1): 37–49.55. Woffendin C., Ranga U., Yang Z. et al: Expression of a protective gene-prolongs survival of T cells in human immunodeficiency virus-infected patients. Proc. Natl. Acad. Sci. USA. 1996; 93(7): 2889–2894.56. Available from: http://www.wiley.com/legacy/wileychi/genmed/clinical/57. van Lunzen J., Glaunsinger T., Stahmer I. et al. Transfer of autologous gene-modified T cells in HIV-infected patients with advanced immunodeficiency and drug-resistant virus. Mol. Ther. 2007; 15: 1024–1033.58. Mitsuyasu R.T., Merigan T.C., Carr A. et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat. Med. 2009; 15(3): 285–292.59. Tebas P., Stein D., Zifchak et al. Prolonged Control of Viremia After Transfer of Autologous CD4 T Cells Genetically Modified with a Lentiviral Vector Expressing Long Antisense to HIV env (VRX496). Abstract. 17th Conference on Retrovirses and Opportunistic Infection, February 2010.60. Lalezari J. et al. Successful and persistent engraftment of ZFN-M-R5-D autologous CD4 T Cells (SB-728-T) in aviremic HIV-infected subjects on HAART. CROI 2011. Abstract 46.61. Hinrichs C.S., Borman Z.A., Gattinoni L. et al. Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. Blood. 2011; 117(3): 808–814.62. Kaneko S., Mastaglio S., Bondanza A. et al. IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T-lymphocytes. Blood 2009; 113(5): 1006–1015.63. Berry L.J., Moeller M., Darcy P.K. Adoptive immunotherapy for cancer: the next generation of gene-engineered immune cells. Tissue Antigens. 2009; 74(4): 277–289.64. van Baarle D., Tsegaye A., Miedema F., Akbar A. Significance of senescence for virus-specific memory T cell responses: rapid ageing during chronic stimulation of the immune system. Immunol Lett. 2005; 97(1): 19–29.65. Cavazzana-Calvo M., Hacein-Bey S., de Saint Basile G. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000; 288(5466): 669–672.66. Aiuti A., Slavin S., Aker M. et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002; 296: 2410–2413.67. Czechowicz A., Kraft D., Weissman I.L., Bhattacharya D. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science. 2007; 318(5854): 1296–1299.68. Glazkova D., Vetchinova A., Zhogina Y. et al. Stable reduction of CCR5 by lentiviral vector-expressed artificial microRNAs. ESGCT and BSGT collaborative Congress. Brighton UK, 2011.69. Glazkova D.V., Vetchinova A.S., Bogoslovskaya E.V. et al. Geneticheskie konstruktsii dlya antiVICh-terapii. Patent na izobretenie RF № 2426788, 01 marta 2010 g. [Genetic constructs for anti-HIV therapy. The patent for the invention of the Russian Federation № 2426788, March 1, 2010].