Quarter Century of Anti-HIV CAR T Cells
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Purpose of Review
A therapy that might cure HIV is a very important goal for the 30–40 million people living with HIV. Chimeric antigen receptor T cells have recently had remarkable success against certain leukemias, and there are reasons to believe they could be successful for HIV. This manuscript summarizes the published research on HIV CAR T cells and reviews the current anti-HIV chimeric antigen receptor strategies.
Research on anti-HIV chimeric antigen receptor T cells has been going on for at least the last 25 years. First- and second-generation anti-HIV chimeric antigen receptors have been developed. First-generation anti-HIV chimeric antigen receptors were studied in clinical trials more than 15 years ago, but did not have meaningful clinical efficacy.
There are some reasons to be optimistic about second-generation anti-HIV chimeric antigen receptor T cells, but they have not yet been tested in vivo.
KeywordsHIV Therapy T cell therapy Chimeric antigen receptor (CAR) HIV cure Review
Dr. Wagner's work on anti-HIV CAR T cells is support by R01 AI118500 and UM1 AI126623.
Compliance with Ethical Standards
Conflict of Interest
Thor A. Wagner declares a patent PCT/US2015/024876 pending to Seattle Children’s Hospital.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
- 3.Ni Z, Knorr DA, Bendzick L, Allred J, Kaufman DS. Expression of chimeric receptor CD4zeta by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo. Stem Cells. 2014;32(4):1021–31. https://doi.org/10.1002/stem.1611.CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Global report: UNAIDS report on the global AIDS epidemic 2012. Joint United Nations Programme on HIV/AIDS (UNAIDS) 2012.Google Scholar
- 6.Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006;43(1):27–34. https://doi.org/10.1097/01.qai.0000233310.90484.16.CrossRefPubMedGoogle Scholar
- 11.Dombrowski JC, Kitahata MM, Van Rompaey SE, Crane HM, Mugavero MJ, Eron JJ, et al. High levels of antiretroviral use and viral suppression among persons in HIV care in the United States, 2010. J Acquir Immune Defic Syndr. 2013;63(3):299–306. https://doi.org/10.1097/QAI.0b013e3182945bc7.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116(20):4099–102. https://doi.org/10.1182/blood-2010-04-281931.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38. https://doi.org/10.1126/scitranslmed.3005930.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Minang JT, Trivett MT, Coren LV, Barsov EV, Piatak M Jr, Ott DE, et al. Nef-mediated MHC class I down-regulation unmasks clonal differences in virus suppression by SIV-specific CD8(+) T cells independent of IFN-gamma and CD107a responses. Virology. 2009;391(1):130–9. https://doi.org/10.1016/j.virol.2009.06.008.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Petrovas C, Chaon B, Ambrozak DR, Price DA, Melenhorst JJ, Hill BJ, et al. Differential association of programmed death-1 and CD57 with ex vivo survival of CD8+ T cells in HIV infection. J Immunol. 2009;183(2):1120–32. https://doi.org/10.4049/jimmunol.0900182.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Kolte L, Gaardbo JC, Skogstrand K, Ryder LP, Ersboll AK, Nielsen SD. Increased levels of regulatory T cells (Tregs) in human immunodeficiency virus-infected patients after 5 years of highly active anti-retroviral therapy may be due to increased thymic production of naive Tregs. Clin Exp Immunol. 2009;155(1):44–52. https://doi.org/10.1111/j.1365-2249.2008.03803.x.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. https://doi.org/10.1126/scitranslmed.3002842.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–20. https://doi.org/10.1182/blood-2011-10-384388.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Bitton N, Verrier F, Debre P, Gorochov G. Characterization of T cell-expressed chimeric receptors with antibody-type specificity for the CD4 binding site of HIV-1 gp120. Eur J Immunol. 1998;28(12):4177–87. https://doi.org/10.1002/(SICI)1521-4141(199812)28:12<4177::AID-IMMU4177>3.0.CO;2-J.Google Scholar
- 48.Liu L, Patel B, Ghanem MH, Bundoc V, Zheng Z, Morgan RA, 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. https://doi.org/10.1128/JVI.00474-15.CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood. 2000;96(3):785–93.PubMedGoogle Scholar
- 53.Deeks SG, Wagner B, Anton PA, Mitsuyasu RT, Scadden DT, Huang C, et al. A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol Ther. 2002;5(6):788–97. https://doi.org/10.1006/mthe.2002.0611.CrossRefPubMedGoogle Scholar
- 54.Maus MV, Fraietta JA, Levine BL, Kalos M, Zhao Y, June CH. Adoptive immunotherapy for cancer or viruses. Annu Rev Immunol. 2014;32:189–225. https://doi.org/10.1146/annurev-immunol-032713-120136.CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Sahu GK, Sango K, Selliah N, Ma Q, Skowron G, Junghans RP. Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells. Virology. 2013;446(1–2):268–75. https://doi.org/10.1016/j.virol.2013.08.002.CrossRefPubMedPubMedCentralGoogle Scholar