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Volume 38 Issue 2
April 2023
    Citation: Hanyu Pan, Xinyi Yang, Jing Wang, Huitong Liang, Zhengtao Jiang, Lin Zhao, Yanan Wang, Zhiming Liang, Xiaoting Shen, Qinru Lin, Yue Liang, Jinglong Yang, Panpan Lu, Yuqi Zhu, Min Li, Pengfei Wang, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu. Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells in vivo .VIROLOGICA SINICA, 2023, 38(2) : 285-295.  http://dx.doi.org/10.1016/j.virs.2023.01.003
    shu

    Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells in vivo

    • a. State Key Laboratory of Genetic Engineering, And Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, 200438, China;

    • b. Shanghai Institute of Infectious Disease and Biosecurity, School of Life Sciences, Fudan University, Shanghai, 200438, China;

    • c. Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;

    • d. Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;

    • e. Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;

    • f. Department of Infectious Diseases and Nursing Research Institution, National Clinical Research Center for Infectious Diseases, The Third People's Hospital of Shenzhen, Shenzhen, 518112, China

    • Corresponding author: Huanzhang Zhu, hzzhu@fudan.edu.cn
    • Received Date: 30 August 2022
      Accepted Date: 11 January 2023
      Available online: 16 January 2023
    • HIV-specific chimeric antigen receptor (CAR) T-cells have been developed to target HIV-1 infected CD4+ T-cells that express HIV Env proteins. However, T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27 (3BE) CAR construct that enabled the expression of programmed cell death protein (PD-1) -blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env. Compared with T cells expressing 3BNC117-CAR alone, 3BE CAR-T cells showed greater cytotoxic activity against HIV Env+ cells with stronger proliferation capability, higher killing efficiency, and enhanced cytokine secretion in the presence of HIV Env-expressing cells. Furthermore, we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env + cells in vivo without the occurrence of severe graft-versus-host disease (GvHD) in NSG mice. These data suggest that we have provided a feasible approach to the generation of “off-the-shelf” anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy, which can be a powerful therapeutic candidate for the functional cure of HIV.
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      1. Alfageme-Abello, O., Porret, R., Perreau, M., Perez, L., Muller, Y.D., 2021. Chimeric antigen receptor T-cell therapy for HIV cure. Curr. Opin. HIV. AIDS. 16, 88-97.

      2. Ali, A., Kitchen, S.G., Chen, I.S.Y., Ng, H.L., Zack, J.A., Yang, O.O., 2016. HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies. J. Virol. 90, 6999-7006.

      3. Archin, N.M., Sung, J.M., Garrido, C., Soriano-Sarabia, N., Margolis, D.M., 2014. Eradicating HIV-1 infection:seeking to clear a persistent pathogen. Nat. Rev. Microbiol. 12, 750-764.

      4. Banerjee, C., Archin, N., Michaels, D., Belkina, A.C., Denis, G. v., Bradner, J., Sebastiani, P., Margolis, D.M., Montano, M., 2012. BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J. Leukoc. Biol. 92, 1147-1154.

      5. Barré-Sinoussi, F., Chermann, J.C., Rey, F., Nugeyre, M.T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vézinet-Brun, F., Rouzioux, C., Rozenbaum, W., Montagnier, L., 1983. Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS). Science (1979). 220, 868-871.

      6. Biasco, L., Scala, S., Basso Ricci, L., Dionisio, F., Baricordi, C., Calabria, A., Giannelli, S., Cieri, N., Barzaghi, F., Pajno, R., Al-Mousa, H., Scarselli, A., Cancrini, C., Bordignon, C., Roncarolo, M.G., Montini, E., Bonini, C., Aiuti, A., 2015. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci. Transl. Med. 7, 273ra13.

      7. Bushara, O., Krogh, K., Weinberg, S.E., Finkelman, B.S., Sun, L., Liao, J., Yang, G.-Y., 2022. Human Immunodeficiency Virus Infection Promotes Human Papillomavirus-Mediated Anal Squamous Carcinogenesis:An Immunologic and Pathobiologic Review. Pathobiology. 89, 1-12.

      8. Caskey, M., Klein, F., Lorenzi, J.C.C., Seaman, M.S., West, A.P., Buckley, N., Kremer, G., Nogueira, L., Braunschweig, M., Scheid, J.F., Horwitz, J.A., Shimeliovich, I., Ben-Avraham, S., Witmer-Pack, M., Platten, M., Lehmann, C., Burke, L.A., Hawthorne, T., Gorelick, R.J., Walker, B.D., Keler, T., Gulick, R.M., Fätkenheuer, G., Schlesinger, S.J., Nussenzweig, M.C., 2015. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 522, 487-491.

      9. Chew, G.M., Fujita, T., Webb, G.M., Burwitz, B.J., Wu, H.L., Reed, J.S., Hammond, K.B., Clayton, K.L., Ishii, N., Abdel-Mohsen, M., Liegler, T., Mitchell, B.I., Hecht, F.M., Ostrowski, M., Shikuma, C.M., Hansen, S.G., Maurer, M., Korman, A.J., Deeks, S.G., Sacha, J.B., Ndhlovu, L.C., 2016. TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection. PLoS. Pathog. 12, e1005349.

      10. CIMINALE, V., FELBER, B.K., CAMPBELL, M., PAVLAKIS, G.N., 1990. A Bioassay for HIV-1 Based on Env-CD4 Interaction. AIDS. Res. Hum. Retroviruses. 6, 1281-1287.

      11. Cooke, K.R., Kobzik, L., Martin, T.R., Brewer, J., Delmonte, J., Crawford, J.M., Ferrara, J.L., 1996. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation:I. The roles of minor H antigens and endotoxin. Blood. 88, 3230-9.

      12. Day, C.L., Kaufmann, D.E., Kiepiela, P., Brown, J.A., Moodley, E.S., Reddy, S., Mackey, E.W., Miller, J.D., Leslie, A.J., DePierres, C., Mncube, Z., Duraiswamy, J., Zhu, B., Eichbaum, Q., Altfeld, M., Wherry, E.J., Coovadia, H.M., Goulder, P.J.R., Klenerman, P., Ahmed, R., Freeman, G.J., Walker, B.D., 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 443, 350-354.

      13. Deeks, S.G., Wagner, B., Anton, P.A., Mitsuyasu, R.T., Scadden, D.T., Huang, C., Macken, C., Richman, D.D., Christopherson, C., June, C.H., Lazar, R., Broad, D.F., Jalali, S., Hege, K.M., 2002. A Phase II Randomized Study of HIV-Specific T-Cell Gene Therapy in Subjects with Undetectable Plasma Viremia on Combination Antiretroviral Therapy. Molecular. Therapy. 5, 788-797.

      14. Dong, H., Strome, S.E., Salomao, D.R., Tamura, H., Hirano, F., Flies, D.B., Roche, P.C., Lu, J., Zhu, G., Tamada, K., Lennon, V.A., Celis, E., Chen, L., 2002. Tumor-associated B7-H1 promotes T-cell apoptosis:A potential mechanism of immune evasion. Nat. Med. 8, 793-800.

      15. Eyquem, J., Mansilla-Soto, J., Giavridis, T., van der Stegen, S.J.C., Hamieh, M., Cunanan, K.M., Odak, A., Gönen, M., Sadelain, M., 2017. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 543, 113-117.

      16. Freeman, G.J., Long, A.J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L.J., Malenkovich, N., Okazaki, T., Byrne, M.C., Horton, H.F., Fouser, L., Carter, L., Ling, V., Bowman, M.R., Carreno, B.M., Collins, M., Wood, C.R., Honjo, T., 2000. Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. Journal of Experimental Medicine. 192, 1027-1034.

      17. Frey, A.B., 2015. Suppression of T cell responses in the tumor microenvironment. Vaccine. 33, 7393-7400.

      18. Fromentin, R., Bakeman, W., Lawani, M.B., Khoury, G., Hartogensis, W., DaFonseca, S., Killian, M., Epling, L., Hoh, R., Sinclair, E., Hecht, F.M., Bacchetti, P., Deeks, S.G., Lewin, S.R., Sékaly, R.-P., Chomont, N., 2016. CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART. PLoS. Pathog. 12, e1005761.

      19. Gattinoni, L., Lugli, E., Ji, Y., Pos, Z., Paulos, C.M., Quigley, M.F., Almeida, J.R., Gostick, E., Yu, Z., Carpenito, C., Wang, E., Douek, D.C., Price, D.A., June, C.H., Marincola, F.M., Roederer, M., Restifo, N.P., 2011. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290-1297.

      20. Ghosh, A., Smith, M., James, S.E., Davila, M.L., Velardi, E., Argyropoulos, K. v, Gunset, G., Perna, F., Kreines, F.M., Levy, E.R., Lieberman, S., Jay, H. v, Tuckett, A.Z., Zakrzewski, J.L., Tan, L., Young, L.F., Takvorian, K., Dudakov, J.A., Jenq, R.R., Hanash, A.M., Motta, A.C.F., Murphy, G.F., Liu, C., Schietinger, A., Sadelain, M., van den Brink, M.R.M., 2017. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat. Med. 23, 242-249.

      21. Grabmeier-Pfistershammer, K., Steinberger, P., Rieger, A., Leitner, J., Kohrgruber, N., 2011. Identification of PD-1 as a Unique Marker for Failing Immune Reconstitution in HIV-1-Infected Patients on Treatment. JAIDS Journal of Acquired Immune Deficiency Syndromes. 56, 118-124.

      22. Hale, M., Mesojednik, T., Romano Ibarra, G.S., Sahni, J., Bernard, A., Sommer, K., Scharenberg, A.M., Rawlings, D.J., Wagner, T.A., 2017. Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells. Molecular. Therapy. 25, 570-579.

      23. Harper, J., Gordon, S., Chan, C.N., Wang, H., Lindemuth, E., Galardi, C., Falcinelli, S.D., Raines, S.L.M., Read, J.L., Nguyen, K., McGary, C.S., Nekorchuk, M., Busman-Sahay, K., Schawalder, J., King, C., Pino, M., Micci, L., Cervasi, B., Jean, S., Sanderson, A., Johns, B., Koblansky, A.A., Amrine-Madsen, H., Lifson, J., Margolis, D.M., Silvestri, G., Bar, K.J., Favre, D., Estes, J.D., Paiardini, M., 2020. CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption. Nat. Med. 26, 519-528.

      24. Herzig, E., Kim, K.C., Packard, T.A., Vardi, N., Schwarzer, R., Gramatica, A., Deeks, S.G., Williams, S.R., Landgraf, K., Killeen, N., Martin, D.W., Weinberger, L.S., Greene, W.C., 2019. Attacking Latent HIV with convertibleCAR-T Cells, a Highly Adaptable Killing Platform. Cell. 179, 880-894.e10.

      25. Hombach, A., Holzinger, A., Abken, H., 2013. The Weal and Woe of Costimulation in the Adoptive Therapy of Cancer with Chimeric Antigen Receptor (CAR)-Redirected T Cells. Curr. Mol. Med. 13, 1079-1088.

      26. Jiang, Z., Liang, H., Pan, H., Liang, Y., Wang, H., Yang, X., Lu, P., Zhang, X., Yang, J., Zhang, D., Shen, X., Wang, J., Liang, Z., Lin, Q., Wang, Y., Zhao, L., Zhong, Y., Lu, H., Zhu, H., 2021. HIV-1-Specific CAR-T Cells With Cell-Intrinsic PD-1 Checkpoint Blockade Enhance Anti-HIV Efficacy in vivo. Front. Microbiol. 12, 684016.

      27. Johnston, Samantha.H., Lobritz, M.A., Nguyen, S., Lassen, K., Delair, S., Posta, F., Bryson, Y.J., Arts, E.J., Chou, T., Lee, B., 2009. A Quantitative Affinity-Profiling System That Reveals Distinct CD4/CCR5 Usage Patterns among Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus Strains. J. Virol. 83, 11016-11026.

      28. Katlama, C., Deeks, S.G., Autran, B., Martinez-Picado, J., van Lunzen, J., Rouzioux, C., Miller, M., Vella, S., Schmitz, J.E., Ahlers, J., Richman, D.D., Sekaly, R.P., 2013. Barriers to a cure for HIV:new ways to target and eradicate HIV-1 reservoirs. The. Lancet. 381, 2109-2117.

      29. Lee, D.W., Kochenderfer, J.N., Stetler-Stevenson, M., Cui, Y.K., Delbrook, C., Feldman, S.A., Fry, T.J., Orentas, R., Sabatino, M., Shah, N.N., Steinberg, S.M., Stroncek, D., Tschernia, N., Yuan, C., Zhang, H., Zhang, L., Rosenberg, S.A., Wayne, A.S., Mackall, C.L., 2015. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults:a phase 1 dose-escalation trial. The. Lancet. 385, 517-528.

      30. Li, Z., Guo, J., Wu, Y., Zhou, Q., 2013. The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation. Nucleic. Acids. Res. 41, 277-287.

      31. Liu, B., Zhang, W., Xia, B., Jing, S., Du, Y., Zou, F., Li, R., Lu, L., Chen, S., Li, Y., Hu, Q., Lin, Y., Zhang, Y., He, Z., Zhang, X., Chen, X., Peng, T., Tang, X., Cai, W., Pan, T., Li, L., Zhang, H., 2021. Broadly neutralizing antibody-derived CAR T cells reduce viral reservoir in individuals infected with HIV-1. Journal of Clinical Investigation. 131, e150211.

      32. Liu, B., Zou, F., Lu, L., Chen, C., He, D., Zhang, X., Tang, X., Liu, C., Li, L., Zhang, H., 2016. Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 + T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy. J. Virol. 90, 9712-9724.

      33. Liu, C., Ma, X., Liu, B., Chen, C., Zhang, H., 2015. HIV-1 functional cure:will the dream come true? BMC. Med. 13, 284.

      34. Liu, Xiaojuan, Zhang, Y., Cheng, C., Cheng, A.W., Zhang, X., Li, N., Xia, C., Wei, X., Liu, Xiang, Wang, H., 2017. CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell. Res. 27, 154-157.

      35. Lugli, E., Dominguez, M.H., Gattinoni, L., Chattopadhyay, P.K., Bolton, D.L., Song, K., Klatt, N.R., Brenchley, J.M., Vaccari, M., Gostick, E., Price, D.A., Waldmann, T.A., Restifo, N.P., Franchini, G., Roederer, M., 2013. Superior T memory stem cell persistence supports long-lived T cell memory. Journal of Clinical Investigation. 123, 594-9.

      36. Ma, S., Li, X., Wang, X., Cheng, L., Li, Z., Zhang, C., Ye, Z., Qian, Q., 2019. Current Progress in CAR-T Cell Therapy for Solid Tumors. Int. J. Biol. Sci. 15, 2548-2560.

      37. Maldini, C.R., Ellis, G.I., Riley, J.L., 2018. CAR T cells for infection, autoimmunity and allotransplantation. Nat. Rev. Immunol. 18, 605-616.

      38. Maude, S.L., Frey, N., Shaw, P.A., Aplenc, R., Barrett, D.M., Bunin, N.J., Chew, A., Gonzalez, V.E., Zheng, Z., Lacey, S.F., Mahnke, Y.D., Melenhorst, J.J., Rheingold, S.R., Shen, A., Teachey, D.T., Levine, B.L., June, C.H., Porter, D.L., Grupp, S.A., 2014. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. New England Journal of Medicine. 371, 1507-1517.

      39. Meier, A., Bagchi, A., Sidhu, H.K., Alter, G., Suscovich, T.J., Kavanagh, D.G., Streeck, H., Brockman, M.A., LeGall, S., Hellman, J., Altfeld, M., 2008. Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands. AIDS. 22, 655-658.

      40. Namdari, H., Rezaei, F., Teymoori-Rad, M., Mortezagholi, S., Sadeghi, A., Akbari, A., 2020. CAR T cells:Living HIV drugs. Rev. Med. Virol. 30, 1-14.

      41. Petrovas, C., Casazza, J.P., Brenchley, J.M., Price, D.A., Gostick, E., Adams, W.C., Precopio, M.L., Schacker, T., Roederer, M., Douek, D.C., Koup, R.A., 2006. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. Journal of Experimental Medicine. 203, 2281-2292.

      42. Poirot, L., Philip, B., Schiffer-Mannioui, C., le Clerre, D., Chion-Sotinel, I., Derniame, S., Potrel, P., Bas, C., Lemaire, L., Galetto, R., Lebuhotel, C., Eyquem, J., Cheung, G.W.-K., Duclert, A., Gouble, A., Arnould, S., Peggs, K., Pule, M., Scharenberg, A.M., Smith, J., 2015. Multiplex Genome-Edited T-cell Manufacturing Platform for "Off-the-Shelf" Adoptive T-cell Immunotherapies. Cancer. Res. 75, 3853-3864.

      43. Porichis, F., Kaufmann, D.E., 2012. Role of PD-1 in HIV Pathogenesis and as Target for Therapy. Curr. HIV/AIDS. Rep. 9, 81-90.

      44. Porichis, F., Kaufmann, D.E., 2011. HIV-specific CD4 T cells and immune control of viral replication. Curr. Opin. HIV. AIDS. 6, 174-180.

      45. Rafiq, S., Yeku, O.O., Jackson, H.J., Purdon, T.J., van Leeuwen, D.G., Drakes, D.J., Song, M., Miele, M.M., Li, Z., Wang, P., Yan, S., Xiang, J., Ma, X., Seshan, V.E., Hendrickson, R.C., Liu, C., Brentjens, R.J., 2018. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847-856.

      46. Ren, J., Liu, X., Fang, C., Jiang, S., June, C.H., Zhao, Y., 2017a. Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition. Clinical Cancer Research. 23, 2255-2266.

      47. Ren, J., Zhang, X., Liu, X., Fang, C., Jiang, S., June, C.H., Zhao, Y., 2017b. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget. 8, 17002-17011.

      48. Roberts, M., Qin, L., Zhang, D., Smith, D., Tran, A., Dull, T., Groopman, J., Capon, D., Byrn, R., Finer, M., 1994. Targeting of human immunodeficiency virus-infected cells by CD8+ T lymphocytes armed with universal T-cell receptors. Blood. 84, 2878-2889.

      49. Rosenberg, S.A., Restifo, N.P., 2015. Adoptive cell transfer as personalized immunotherapy for human cancer. Science (1979). 348, 62-68.

      50. Ruelas, D.S., Greene, W.C., 2013. An Integrated Overview of HIV-1 Latency. Cell. 155, 519-529.

      51. Scheid, J.F., Horwitz, J.A., Bar-On, Y., Kreider, E.F., Lu, C.-L., Lorenzi, J.C.C., Feldmann, A., Braunschweig, M., Nogueira, L., Oliveira, T., Shimeliovich, I., Patel, R., Burke, L., Cohen, Y.Z., Hadrigan, S., Settler, A., Witmer-Pack, M., West,, Anthony P., Juelg, B., Keler, T., Hawthorne, T., Zingman, B., Gulick, R.M., Pfeifer, N., Learn, G.H., Seaman, M.S., Bjorkman, P.J., Klein, F., Schlesinger, S.J., Walker, B.D., Hahn, B.H., Nussenzweig, M.C., Caskey, M., 2016. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature. 535, 556-560.

      52. Scholler, J., Brady, T.L., Binder-Scholl, G., Hwang, W.-T., Plesa, G., Hege, K.M., Vogel, A.N., Kalos, M., Riley, J.L., Deeks, S.G., Mitsuyasu, R.T., Bernstein, W.B., Aronson, N.E., Levine, B.L., Bushman, F.D., June, C.H., 2012. Decade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T Cells. Sci. Transl. Med. 4, 132ra53.

      53. Sommermeyer, D., Hudecek, M., Kosasih, P.L., Gogishvili, T., Maloney, D.G., Turtle, C.J., Riddell, S.R., 2016. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 30, 492-500.

      54. Topalian, S.L., Drake, C.G., Pardoll, D.M., 2012. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 24, 207-212.

      55. Torikai, H., Reik, A., Liu, P.-Q., Zhou, Y., Zhang, L., Maiti, S., Huls, H., Miller, J.C., Kebriaei, P., Rabinovitch, B., Lee, D.A., Champlin, R.E., Bonini, C., Naldini, L., Rebar, E.J., Gregory, P.D., Holmes, M.C., Cooper, L.J.N., 2012. A foundation for universal T-cell based immunotherapy:T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood. 119, 5697-5705.

      56. Trautmann, L., Janbazian, L., Chomont, N., Said, E.A., Gimmig, S., Bessette, B., Boulassel, M.-R., Delwart, E., Sepulveda, H., Balderas, R.S., Routy, J.-P., Haddad, E.K., Sekaly, R.-P., 2006. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198-1202.

      57. Velu, V., Titanji, K., Zhu, B., Husain, S., Pladevega, A., Lai, L., Vanderford, T.H., Chennareddi, L., Silvestri, G., Freeman, G.J., Ahmed, R., Amara, R.R., 2009. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 458, 206-210.

      58. Zhen, A., Carrillo, M.A., Mu, W., Rezek, V., Martin, H., Hamid, P., Chen, I.S.Y., Yang, O.O., Zack, J.A., Kitchen, S.G., 2021a. Robust CAR-T memory formation and function via hematopoietic stem cell delivery. PLoS. Pathog. 17, e1009404.

      59. Zhen, A., Carrillo, M.A., Mu, W., Rezek, V., Martin, H., Hamid, P., Chen, I.S.Y., Yang, O.O., Zack, J.A., Kitchen, S.G., 2021b. Robust CAR-T memory formation and function via hematopoietic stem cell delivery. PLoS. Pathog. 17, e1009404.

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      Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells in vivo

        Corresponding author: Huanzhang Zhu, hzzhu@fudan.edu.cn
      • a. State Key Laboratory of Genetic Engineering, And Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, 200438, China;
      • b. Shanghai Institute of Infectious Disease and Biosecurity, School of Life Sciences, Fudan University, Shanghai, 200438, China;
      • c. Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;
      • d. Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;
      • e. Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;
      • f. Department of Infectious Diseases and Nursing Research Institution, National Clinical Research Center for Infectious Diseases, The Third People's Hospital of Shenzhen, Shenzhen, 518112, China
      • Received Date: 30 August 2022
      • Accepted Date: 11 January 2023

      Abstract: HIV-specific chimeric antigen receptor (CAR) T-cells have been developed to target HIV-1 infected CD4+ T-cells that express HIV Env proteins. However, T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27 (3BE) CAR construct that enabled the expression of programmed cell death protein (PD-1) -blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env. Compared with T cells expressing 3BNC117-CAR alone, 3BE CAR-T cells showed greater cytotoxic activity against HIV Env+ cells with stronger proliferation capability, higher killing efficiency, and enhanced cytokine secretion in the presence of HIV Env-expressing cells. Furthermore, we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env + cells in vivo without the occurrence of severe graft-versus-host disease (GvHD) in NSG mice. These data suggest that we have provided a feasible approach to the generation of “off-the-shelf” anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy, which can be a powerful therapeutic candidate for the functional cure of HIV.

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