OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press103510.17650/1818-8346-2025-20-2-115-125CURRENT ASPECTS AND THE FUTURE OF GENE-CELL IMMUNOTHERAPY IN THE TREATMENT OF HIV INFECTIONАКТУАЛЬНЫЕ АСПЕКТЫ И БУДУЩЕЕ ГЕННО-КЛЕТОЧНОЙ ИММУНОТЕРАПИИ В ЛЕЧЕНИИ ВИЧ-ИНФЕКЦИИCurrent trends and future of gene-cell immunotherapy in the treatment of HIV infectionТекущие тенденции и будущее генно-клеточной иммунотерапии в лечении ВИЧ-инфекцииhttps://orcid.org/0000-0001-6158-233XFaenkoA. P.ФаенкоА. П.
Russian Federation

Aleksandr Pavlovich Faenko 

Build. 1, 1 Novogireevskaya St., Moscow 111123

Александр Павлович Фаенко 

111123 Москва, ул. Новогиреевская, 1, корп. 1 

a.faenko@mknc.ruhttps://orcid.org/0000-0001-9673-1067DudinaG. A.ДудинаГ. А.
Russian Federation

Build. 1, 1 Novogireevskaya St., Moscow 111123

111123 Москва, ул. Новогиреевская, 1, корп. 1 

https://orcid.org/0000-0002-2789-4791MabudzadeCh. K.МабудзадеЧ. К.
Russian Federation

Build. 1, 1 Novogireevskaya St., Moscow 111123

111123 Москва, ул. Новогиреевская, 1, корп. 1 

https://orcid.org/0009-0006-9816-1858OgannisyanA. A.ОганнисянА. А.
Russian Federation

Build. 1, 1 Novogireevskaya St., Moscow 111123

111123 Москва, ул. Новогиреевская, 1, корп. 1 

Moscow Clinical Scientific and Practical Center named after A.S. Loginov, Moscow Healthcare DepartmentГБУЗ г. Москвы «Московский клинический научно-практический центр им. А.С. Логинова Департамента здравоохранения г. Москвы»220520252021151252005202520052025https://oncohematology.abvpress.ru/ongm/article/view/1035

Despite significant advancements in antiretroviral therapy, HIV viral reservoirs continue to persist even in patients receiving combination therapy. In recent years, promising results have emerged in HIV treatment, including two cases of functional cure known as the “Berlin patient” and the “London patient”, both of whom received allogeneic hematopoietic stem cell transplants from donors with the CCR5Δ32 mutation. These cases underscore the importance of genetically modified stem cells in achieving resistance to HIV. The development of genome editing methods, such as CRISPR/Cas9, opens new horizons for creating targeted therapies aimed at eliminating the virus from infected cells. Research also shows promise in the application of cell immunotherapy, including CAR T-cells and NK cells, which may enhance control over HIV due to their ability to recognize and destroy infected cells. In light of these achievements, research in gene therapy targeting co-receptors, as well as new approaches such as virus activation and elimination methods, represents critical steps toward achieving a functional cure for HIV.This review discusses progress in genetic manipulation, immunotherapy, and the adaptation of conditioning regimens to develop effective treatment strategies for a broad range of HIV patients.

Несмотря на значительные достижения в области антиретровирусной терапии, резервуары вируса иммунодефицита человека (ВИЧ) продолжают сохраняться даже у пациентов, получающих комбинированную терапию. В последние годы наблюдаются обнадеживающие результаты в лечении ВИЧ, включая 2 случая функционального излечения, известные как «Берлинский пациент» и «Лондонский пациент», которые получили аллогенную трансплантацию гемопоэтических стволовых клеток от доноров с мутацией CCR5Δ32. Эти случаи подчеркивают важность генетически модифицированных стволовых клеток для достижения ВИЧ-устойчивости. Разработка методов редактирования генома, таких как CRISPR/Cas9, открывает новые горизонты в создании целевой терапии, направленной на удаление вируса из инфицированных клеток. Результаты исследований также показывают перспективы в применении клеточной иммунотерапии, включая T-клетки с химерными антигенными рецепторами и естественные киллеры, которые могут улучшить контроль над ВИЧ благодаря способности распознавать и уничтожать инфицированные клетки.В свете этих достижений исследования в области генной терапии, нацеленной на корецепторы, а также новые подходы, такие как методы активации и элиминации вируса, представляют собой важные шаги в стремлении к функциональному излечению ВИЧ. В обзоре рассматривается прогресс в области генетических манипуляций, иммунотерапии и адаптации схем кондиционирования для разработки эффективных стратегий лечения ВИЧ у широкого круга пациентов.

HIVcell immunotherapyCAR-TCAR-NKCCR5ВИЧклеточная терапияCAR-TCAR-NKCCR5State report “On the state of sanitary and epidemiological welfare of the population in Russian Federation in 2023”. 2024. Available at: https://oncology-association.ru/wp-content/uploads/2024/08/zis-2023-elektronnaya-versiya.pdf. (In Russ.).Государственный доклад «О состоянии санитарно-эпидемиологического благополучия населения в Российской Федерации в 2023 году». 2024. Доступно по: https://www.rospotrebnadzor.ru/upload/iblock/fbc/sd3prfszlc9c2r4xbmsb7o3us38nrvpk/Gosudarstvennyy-doklad-_O-sostoyanii-sanitarno_epidemiologicheskogo-blagopoluchiya-naseleniya-v-Rossiyskoy-Federatsii-v-2023-godu_pdfAdgamov R.R., Antonova A.A., Ogarkova D.A. et al. HIV-infection in the Russian Federation: current diagnostic trends. VICH- infektsiya i immunosupressii = HIV Infection and Immunosuppressive Disorders 2024;16(1):45–59. (In Russ.). DOI: 10.22328/2077-9828-2024-16-1-45-59Адгамов Р.Р., Антонова А.А., Огаркова Д.А. и др. ВИЧ-инфекция в Российской Федерации: современные тенденции диагностики. ВИЧ-инфекция и иммуносупрессии 2024;16(1):45–59. DOI: 10.22328/2077-9828-2024-16-1-45-59Bongiovanni M., Casana M., Tincati C., d’Arminio Monforte A. Treatment interruptions in HIV-infected subjects. J Antimicrob Chemother 2006;58(3):502–5. DOI: 10.1093/jac/dkl268Wearne N., Davidson B., Blockman M. et al. HIV, drugs and the kidney. Drugs Context 2020;9:2019-11-1. DOI: 10.7573/dic.2019-11-1Nachega J.B., Hsu A.J., Uthman O.A. et al. Antiretroviral therapy adherence and drug-drug interactions in the aging HIV population. AIDS 2012;26(1):39–53. DOI: 10.1097/QAD.0b013e32835584eaPavlova A.A., Maschan M.A., Ponomarev V.B. Adaptive immunotherapy with genetically modified T-lymphocytes expressing chimeric antigenic receptors. Onkogematologiya = Oncohematology 2017;12(1):17–32. (In Russ.). DOI: 10.17650/1818-8346-2017-12-1-17-32Павлова А.А., Масчан М.А., Пономарев В.Б. Адоптивная иммунотерапия генетически модифицированными Т-лимфоцитами, экспрессирующими химерные антигенные рецепторы. Онкогематология 2017;12(1):17–32. DOI: 10.17650/1818-8346-2017-12-1-17-32Zhang Y., Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor- infiltrating immune cells and their therapeutic implications. Cell Mol Immunol 2020;17(8):807–21. DOI: 10.1038/s41423-020-0488-6Barré-Sinoussi F., Chermann J.C., Rey F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220(4599):868–71. DOI: 10.1126/science.6189183Van Heuvel Y., Schatz S., Rosengarten J.F., Stitz J. Infectious RNA: human immunodeficiency virus (HIV) biology, therapeutic intervention, and the quest for a vaccine. Toxins (Basel) 2022;14(2):138. DOI: 10.3390/toxins14020138Reeves J.D., Doms R.W. Human immunodeficiency virus type 2. J Gen Virol 2002;83(6):1253–65. DOI: 10.1099/0022-1317-83-6-1253Parkhomenko Yu.G., Zyuzya Yu.R., Mazus A.I. Morphological aspects of HIV infection. Moscow: Litterra, 2016. 168 p. (In Russ.).Пархоменко Ю.Г., Зюзя Ю.Р., Мазус А.И. Морфологические аспекты ВИЧ-инфекции. М.: Литтерра, 2016. 168 с.Allers K., Schneider T. CCR5Δ32 mutation and HIV infection: basis for curative HIV therapy. Current Opin Virol 2015;14:24–9. DOI: 10.1016/j.coviro.2015.06.007Liu R., Paxton W.A., 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(3):367–77. DOI: 10.1016/s0092-8674(00)80110-5Walli R., Reinhart B., Luckow B. et al. HIV-1-infected long-term slow progressors heterozygous for delta32-CCR5 show significantly lower plasma viral load than wild-type slow progressors. J Acquir Immune Defic Syndr Hum Retrovirol 1998;18(3):229–33. DOI: 10.1097/00042560-199807010-00005Hütter G., Nowak D., Mossner M. et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009;360(7):692–8. DOI: 10.1056/NEJMoa0802905Gupta R.K., Abdul-Jawad S., McCoy L.E. et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 2019;568(7751):244–8. DOI: 10.1038/s41586-019-1027-4Gupta R.K., Peppa D., Hill A.L. et al. Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report. Lancet HIV 2020;7(5):340–7. DOI: 10.1016/S2352-3018(20)30069-2Sáez-Cirión A., Mamez A.C., Avettand-Fenoel V. et al. Sustained HIV remission after allogeneic hematopoietic stem cell transplantation with wild-type CCR5 donor cells. Nat Med 2024;30(12):3544–54. DOI: 10.1038/s41591-024-03277-zKordelas L., Verheyen J., Beelen D.W. et al. Shift of HIV tropism in stem-cell transplantation with CCR5 Delta32 mutation. N Engl J Med 2014;371(9):880–2. DOI: 10.1056/NEJMc1405805Henrich T.J., Hanhauser E., Marty F.M. et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med 2014;161(5):319–27. DOI: 10.7326/M14-1027Tebas P., Stein D., Tang W.W. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 2014;370(10):901–10. DOI: 10.1056/NEJMoa1300662Kiem H.P., Jerome K.R., Deeks S.G., McCune J.M. Hematopoietic-stem-cell-based gene therapy for HIV disease. Cell Stem Cell 2012;10(2):137–47. DOI: 10.1016/j.stem.2011.12.015Yukl S.A., Boritz E., Busch M. et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog 2013;9(5):e1003347. DOI: 10.1371/journal.ppat.1003347Symons J., Chopra A., Malatinkova E. et al. HIV integration sites in latently infected cell lines: evidence of ongoing replication [published correction appears in Retrovirology 2017;14(1):23]. Retrovirology 2017;14(1):2. DOI: 10.1186/s12977-016-0325-2Ji H., Lu P., Liu B. et al. Zinc-finger nucleases induced by HIV-1 tat excise HIV-1 from the host genome in infected and latently infected cells. Mol Ther Nucleic Acids 2018;12:67–74. DOI: 10.1016/j.omtn.2018.04.014Joung J.K., Sander J.D. TALENs: a widely applicable technology for targeted genome editing. Nat Rev Mol Cell Biol 2013;14(1):49–55. DOI: 10.1038/nrm3486Dash P.K., Kaminski R., Bella R. et al. Sequential LASER ART and CRISPR treatments eliminate HIV-1 in a subset of infected humanized mice. Nat Commun 2019;10(1):2753. DOI: 10.1038/s41467-019-10366-yPerez 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):808–16. DOI: 10.1038/nbt1410Holt 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):839–47. DOI: 10.1038/nbt.1663Cai Y., Bak R.O., Mikkelsen J.G. Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases. Elife 2014;3:e01911. DOI: 10.7554/eLife.01911ClinicalTrials.gov (NCT02500849). Safety study of zinc finger nuclease CCR5-modified hematopoietic stem/progenitor cells in HIV-1 infected patients. Available at: https://clinicaltrials.gov/study/NCT02500849?intr=NCT02500849&rank=1Mussolino C., Alzubi J., Fine E.J. et al. TALENs facilitate targeted genome editing in human cells with high specificity and low cytotoxicity. Nucleic Acids Res 2014;42(10):6762–73. DOI: 10.1093/nar/gku305Yu A.Q., Ding Y., Lu Z.Y. et al. TALENs-mediated homozygous CCR5Δ32 mutations endow CD4+ U87 cells with resistance against HIV­1 infection. Mol Med Rep 2018;17(1):243–9. DOI: 10.3892/mmr.2017.7889Romito M., Juillerat A., Kok Y.L. et al. Preclinical evaluation of a novel TALEN targeting CCR5 confirms efficacy and safety in conferring resistance to HIV-1 infection. Biotechnol J 2021;16(1):e2000023. DOI: 10.1002/biot.202000023Nerys-Junior A., Braga-Dias L.P., Pezzuto P. et al. Comparison of the editing patterns and editing efficiencies of TALEN and CRISPR-Cas9 when targeting the human CCR5 gene. Genet Mol Biol 2018;41(1):167–79. DOI: 10.1590/1678-4685-GMB-2017-0065Teque F., Ye L., Xie F. et al. Genetically-edited induced pluripotent stem cells derived from HIV-1-infected patients on therapy can give rise to immune cells resistant to HIV-1 infection. AIDS 2020;34(8):1141–9. DOI: 10.1097/QAD.0000000000002539Mandal P.K., Ferreira L.M., 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. DOI: 10.1016/j.stem.2014.10.004Xu L., Yang H., Gao Y. et al. CRISPR/Cas9-mediated CCR5 ablation in human hematopoietic stem/progenitor cells confers HIV-1 resistance in vivo. Mol Ther 2017;25(8):1782–9. DOI: 10.1016/j.ymthe.2017.04.027Xu L., Wang J., Liu Y. et al. CRISPR-edited stem cells in a patient with HIV and acute lymphocytic leukemia. N Engl J Med 2019;381(13):1240–7. DOI: 10.1056/NEJMoa1817426Didigu C.A., Wilen C.B., Wang J. et al. Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection. Blood 2014;123(1):61–9. DOI: 10.1182/blood-2013-08-521229Yu S., Yao Y., Xiao H. et al. Simultaneous knockout of CXCR4 and CCR5 genes in CD4+ T cells via CRISPR/Cas9 confers resistance to both X4- and R5-tropic human immunodeficiency virus type 1 infection. Hum Gene Ther 2018;29(1):51–67. DOI: 10.1089/hum.2017.032Liu Z., Chen S., Jin X. et al. Genome editing of the HIV co-receptors CCR5 and CXCR4 by CRISPR-Cas9 protects CD4+ T cells from HIV-1 infection. Cell Biosci 2017;7:47. DOI: 10.1186/s13578-017-0174-2Ma Q., Jones D., Borghesani P.R. et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 1998;95(16):9448–53. DOI: 10.1073/pnas.95.16.9448Dar A., Kollet O., Lapidot T. Mutual, reciprocal SDF-1/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in NOD/ SCID chimeric mice. Exp Hematol 2006;34(8):967–75. DOI: 10.1016/j.exphem.2006.04.002Liu Y., Zhou J., Pan J.A. et al. A novel approach to block HIV-1 coreceptor CXCR4 in non-toxic manner. Mol Biotechnol 2014;56(10):890–902. DOI: 10.1007/s12033-014-9768-7Wang Z., Pan Q., Gendron P. et al. CRISPR/Cas9-derived mutations both inhibit HIV-1 replication and accelerate viral escape. Cell Rep 2016;15(3):481–9. DOI: 10.1016/j.celrep.2016.03.042Kitawi R., Ledger S., Kelleher A.D., Ahlenstiel C.L. Advances in HIV gene therapy. Int J Mol Sci 2024;25(5):2771. DOI: 10.3390/ijms25052771Abramson J.S., Irwin K.E., Frigault M.J. et al. Successful anti-CD19 CAR T-cell therapy in HIV-infected patients with refractory high-grade B-cell lymphoma. Cancer 2019;125(21):3692–8. DOI: 10.1002/cncr.32411Scholler J., Brady T.L., Binder-Scholl G. et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med 2012;4(132):132ra53. DOI: 10.1126/scitranslmed.3003761Liu L., Patel B., Ghanem M.H. et al. Novel CD4-based bispecific chimeric antigen receptor designed for enhanced anti-HIV potency and absence of HIV entry receptor activity. J Virol 2015;89(13):6685–94. DOI: 10.1128/JVI.00474-15Neidleman J., Luo X., Frouard J. et al. Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir. Elife 2020;9:e60933. DOI: 10.7554/eLife.60933Connick E., Mattila T., Folkvord J.M. et al. CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J Immunol 2007;178(11):6975–83. DOI: 10.4049/jimmunol.178.11.6975Anthony-Gonda K., Bardhi A., Ray A. et al. Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model. Sci Transl Med 2019;11(504):eaav5685. DOI: 10.1126/scitranslmed.aav5685Anthony-Gonda K., Ray A., Su H. et al. In vivo killing of primary HIV-infected cells by peripheral-injected early memory-enriched anti-HIV duoCAR T cells. JCI Insight 2022;7(21):e161698. DOI: 10.1172/jci.insight.161698ClinicalTrials.gov (NCT04648046). CAR-T cells for HIV infection. Available at: https://clinicaltrials.gov/study/NCT04648046?cond=HIV&term=CAR%20T%20cells&limit=25&page=1&rank=5#publicationsAnderko R.R., Mailliard R.B. Mapping the interplay between NK cells and HIV: therapeutic implications. J Leukoc Biol 2023;113(2):109–38. DOI: 10.1093/jleuko/qiac007Perera Molligoda Arachchige A.S. NK cell-based therapies for HIV infection: investigating current advances and future possibilities. J Leukoc Biol 2022;111(4):921–31. DOI: 10.1002/JLB.5RU0821-412RRLim R.M., Rong L., Zhen A., Xie J. A universal CAR-NK cell targeting various epitopes of HIV-1 gp160. ACS Chem Biol 2020;15(8):2299–310. DOI: 10.1021/acschembio.0c00537Mehta R.S., Randolph B., Daher M., Rezvani K. NK cell therapy for hematologic malignancies. Int J Hematol 2018;107(3):262–70. DOI: 10.1007/s12185-018-2407-5Abate-Daga D., Davila M.L. CAR models: next-generation CAR modifications for enhanced T-cell function. Mol Ther Oncolytics 2016;3:16014. DOI: 10.1038/mto.2016.14Imai C., Iwamoto S., Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 2005;106(1):376–83. DOI: 10.1182/blood-2004-12-4797Töpfer K., Cartellieri M., Michen S. et al. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. J Immunol 2015;194(7):3201–12. DOI: 10.4049/jimmunol.1400330Carr W.H., Rosen D.B., Arase H. et al. Cutting Edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation. J Immunol 2007;178(2):647–51. DOI: 10.4049/jimmunol.178.2.647