Advertisement

New approaches for the enhancement of chimeric antigen receptors for the treatment of HIV

  • Mayra A. Carrillo
    Affiliations
    Division of Hematology & Oncology, Department of Medicine, UCLA AIDS Institute, David Geffen School of Medicine University of California, Los Angeles, Calif
    Search for articles by this author
  • Anjie Zhen
    Affiliations
    Division of Hematology & Oncology, Department of Medicine, UCLA AIDS Institute, David Geffen School of Medicine University of California, Los Angeles, Calif
    Search for articles by this author
  • Jerome A. Zack
    Affiliations
    Division of Hematology & Oncology, Department of Medicine, UCLA AIDS Institute, David Geffen School of Medicine University of California, Los Angeles, Calif

    Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Calif
    Search for articles by this author
  • Scott G. Kitchen
    Correspondence
    Reprint requests: Scott G. Kitchen, Division of Hematology & Oncology, Department of Medicine, UCLA AIDS Institute, David Geffen School of Medicine University of California, Los Angeles, CA 90095
    Affiliations
    Division of Hematology & Oncology, Department of Medicine, UCLA AIDS Institute, David Geffen School of Medicine University of California, Los Angeles, Calif
    Search for articles by this author
      HIV infection continues to be a life-long chronic disease in spite of the success of antiretroviral therapy (ART) in controlling viral replication and preventing disease progression. However, because of the high cost of treatment, severe side effects, and inefficiency in curing the disease with ART, there is a call for alternative therapies that will provide a functional cure for HIV. Cytotoxic T lymphocytes (CTLs) are vital in the control and clearance of viral infections and therefore immune-based therapies have attempted to engineer HIV-specific CTLs that would be able to clear the infection from the body. The development of chimeric antigen receptors (CARs) provides an opportunity to engineer superior HIV-specific CTLs that will be independent of the major histocompatibility complex for target recognition. A CD4-based CAR has been previously tested in clinical trials to test the antiviral efficacy of peripheral T cells armed with this CD4-based CAR. The results from these clinical trials showed the safety and feasibility of CAR T cell therapy for HIV infection; however, minimal antiviral efficacy was seen. In this review, we will discuss the various strategies being developed to enhance the therapeutic potency of anti-HIV CARs with the goal of generating superior antiviral responses that will lead to life-long HIV immunity and clearance of the virus from the body.

      Abbreviations:

      bNAbs (broadly neutralizing antibodies), CAR (chimeric antigen receptor), CTL (cytotoxic T lymphocyte), HSC (hematopoietic stem cell), TCR (T cell receptor)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Volberding P.A.
        • Deeks S.G.
        Antiretroviral therapy and management of HIV infection.
        Lancet. 2010; 376: 49-62
        • Bruner K.M.
        • Murray A.J.
        • Pollack R.A.
        • et al.
        Defective proviruses rapidly accumulate during acute HIV-1 infection.
        Nat Med. 2016; 22: 1043-1049
        • Dahabieh M.S.
        • Battivelli E.
        • Verdin E.
        Understanding HIV latency: the road to an HIV cure.
        Annu Rev Med. 2015; 66: 407-421
        • Deng K.
        • Pertea M.
        • Rongvaux A.
        • et al.
        Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations.
        Nature. 2015; 517: 381-385
        • Schmitz J.E.
        • Kuroda M.J.
        • Santra S.
        • et al.
        Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.
        Science. 1999; 283: 857-860
        • Jin X.
        • Bauer D.E.
        • Tuttleton S.E.
        • et al.
        Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques.
        J Exp Med. 1999; 189: 991-998
        • Matano T.
        • Shibata R.
        • Siemon C.
        • Connors M.
        • Lane H.C.
        • Martin M.A.
        Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques.
        J Virol. 1998; 72: 164-169
        • Rosenberg E.S.
        • Billingsley J.M.
        • Caliendo A.M.
        • et al.
        Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.
        Science. 1997; 278: 1447-1450
        • Lichterfeld M.
        • Kaufmann D.E.
        • Yu X.G.
        • et al.
        Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells.
        J Exp Med. 2004; 200: 701-712
        • Chevalier M.F.
        • Julg B.
        • Pyo A.
        • et al.
        HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function.
        J Virol. 2011; 85: 733-741
        • Koenig S.
        • Conley A.J.
        • Brewah Y.A.
        • et al.
        Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression.
        Nat Med. 1995; 1: 330-336
        • Lieberman J.
        • Skolnik P.R.
        • Parkerson 3rd, G.R.
        • et al.
        Safety of autologous, ex vivo-expanded human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte infusion in HIV-infected patients.
        Blood. 1997; 90: 2196-2206
        • Brodie S.J.
        • Lewinsohn D.A.
        • Patterson B.K.
        • et al.
        In vivo migration and function of transferred HIV-1-specific cytotoxic T cells.
        Nat Med. 1999; 5: 34-41
        • McKinney D.M.
        • Lewinsohn D.A.
        • Riddell S.R.
        • Greenberg P.D.
        • Mosier D.E.
        The antiviral activity of HIV-specific CD8+ CTL clones is limited by elimination due to encounter with HIV-infected targets.
        J Immunol. 1999; 163: 861-867
        • Riddell S.R.
        • Elliott M.
        • Lewinsohn D.A.
        • et al.
        T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients.
        Nat Med. 1996; 2: 216-223
        • Lam S.
        • Sung J.
        • Cruz C.
        • et al.
        Broadly-specific cytotoxic T cells targeting multiple HIV antigens are expanded from HIV+ patients: implications for immunotherapy.
        Mol Ther. 2015; 23: 387-395
        • Sung J.A.
        • Lam S.
        • Garrido C.
        • et al.
        Expanded cytotoxic T-cell lymphocytes target the latent HIV reservoir.
        J Infect Dis. 2015; 212: 258-263
        • Cooper L.J.
        • Kalos M.
        • Lewinsohn D.A.
        • Riddell S.R.
        • Greenberg P.D.
        Transfer of specificity for human immunodeficiency virus type 1 into primary human T lymphocytes by introduction of T-cell receptor genes.
        J Virol. 2000; 74: 8207-8212
        • Varela-Rohena A.
        • Molloy P.E.
        • Dunn S.M.
        • et al.
        Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor.
        Nat Med. 2008; 14: 1390-1395
        • Joseph A.
        • Zheng J.H.
        • Follenzi A.
        • et al.
        Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV-1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity.
        J Virol. 2008; 82: 3078-3089
        • Hofmann C.
        • Harrer T.
        • Kubesch V.
        • et al.
        Generation of HIV-1-specific T cells by electroporation of T-cell receptor RNA.
        AIDS. 2008; 22: 1577-1582
        • Kitchen S.G.
        • Bennett M.
        • Galic Z.
        • et al.
        Engineering antigen-specific T cells from genetically modified human hematopoietic stem cells in immunodeficient mice.
        PLoS One. 2009; 4: e8208
        • Kitchen S.G.
        • Levin B.R.
        • Bristol G.
        • et al.
        In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells.
        PLoS Pathog. 2012; 8: e1002649
        • Johnson W.E.
        • Desrosiers R.C.
        Viral persistence: HIV's strategies of immune system evasion.
        Annu Rev Med. 2002; 53: 499-518
        • Morgan R.A.
        • Dudley M.E.
        • Wunderlich J.R.
        • et al.
        Cancer regression in patients after transfer of genetically engineered lymphocytes.
        Science. 2006; 314: 126-129
        • Rosenberg S.A.
        Of mice, not men: no evidence for graft-versus-host disease in humans receiving T-cell receptor-transduced autologous T cells.
        Mol Ther. 2010; 18: 1744-1745
        • Cameron B.J.
        • Gerry A.B.
        • Dukes J.
        • et al.
        Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells.
        Sci Transl Med. 2013; 5: 197ra03
        • Fesnak A.D.
        • June C.H.
        • Levine B.L.
        Engineered T cells: the promise and challenges of cancer immunotherapy.
        Nat Rev Cancer. 2016; 16: 566-581
        • Grupp S.A.
        • Kalos M.
        • Barrett D.
        • et al.
        Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
        N Engl J Med. 2013; 368: 1509-1518
        • Maude S.L.
        • Frey N.
        • Shaw P.A.
        • et al.
        Chimeric antigen receptor T cells for sustained remissions in leukemia.
        N Engl J Med. 2014; 371: 1507-1517
        • Maude S.L.
        • Teachey D.T.
        • Porter D.L.
        • Grupp S.A.
        CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.
        Blood. 2015; 125: 4017-4023
        • Brentjens R.J.
        • Davila M.L.
        • Riviere I.
        • et al.
        CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.
        Sci Transl Med. 2013; 5: 177ra38
        • Davila M.L.
        • Riviere I.
        • Wang X.
        • et al.
        Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia.
        Sci Transl Med. 2014; 6: 224ra25
        • Imai C.
        • Mihara K.
        • Andreansky M.
        • et al.
        Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia.
        Leukemia. 2004; 18: 676-684
        • Finney H.M.
        • Lawson A.D.
        • Bebbington C.R.
        • Weir A.N.
        Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product.
        J Immunol. 1998; 161: 2791-2797
        • Shen C.J.
        • Yang Y.X.
        • Han E.Q.
        • et al.
        Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma.
        J Hematol Oncol. 2013; 6: 33
        • Pule M.A.
        • Straathof K.C.
        • Dotti G.
        • Heslop H.E.
        • Rooney C.M.
        • Brenner M.K.
        A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells.
        Mol Ther. 2005; 12: 933-941
        • Finney H.M.
        • Akbar A.N.
        • Lawson A.D.
        Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain.
        J Immunol. 2004; 172: 104-113
        • Wang J.
        • Jensen M.
        • Lin Y.
        • et al.
        Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains.
        Hum Gene Ther. 2007; 18: 712-725
        • Tang X.Y.
        • Sun Y.
        • Zhang A.
        • et al.
        Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol.
        BMJ Open. 2016; 6: e013904
        • Savoldo B.
        • Ramos C.A.
        • Liu E.
        • et al.
        CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients.
        J Clin Invest. 2011; 121: 1822-1826
        • Frey N.V.
        • Porter D.L.
        The promise of chimeric antigen receptor T-cell therapy.
        Oncology (Williston Park). 2016; 30 (890): 880-888
        • Walker R.E.
        • Bechtel C.M.
        • Natarajan V.
        • et al.
        Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection.
        Blood. 2000; 96: 467-474
        • Mitsuyasu R.T.
        • Anton P.A.
        • Deeks S.G.
        • 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: 785-793
        • Deeks S.G.
        • Wagner B.
        • Anton P.A.
        • 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: 788-797
        • Yang O.O.
        • Tran A.C.
        • Kalams S.A.
        • Johnson R.P.
        • Roberts M.R.
        • Walker B.D.
        Lysis of HIV-1-infected cells and inhibition of viral replication by universal receptor T cells.
        Proc Natl Acad Sci U S A. 1997; 94: 11478-11483
        • Roberts M.R.
        • Qin L.
        • Zhang D.
        • et al.
        Targeting of human immunodeficiency virus-infected cells by CD8+ T lymphocytes armed with universal T-cell receptors.
        Blood. 1994; 84: 2878-2889
        • Brudno J.N.
        • Kochenderfer J.N.
        Toxicities of chimeric antigen receptor T cells: recognition and management.
        Blood. 2016; 127: 3321-3330
        • Scholler 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: 132ra53
        • Zhen A.
        • Kamata M.
        • Rezek V.
        • et al.
        HIV-specific immunity derived from chimeric antigen receptor-engineered stem cells.
        Mol Ther. 2015; 23: 1358-1367
        • Kamata M.
        • Kim P.Y.
        • Ng H.L.
        • et al.
        Ectopic expression of anti-HIV-1 shRNAs protects CD8(+) T cells modified with CD4zeta CAR from HIV-1 infection and alleviates impairment of cell proliferation.
        Biochem Biophys Res Commun. 2015; 463: 216-221
        • Cha E.
        • Graham L.
        • Manjili M.H.
        • Bear H.D.
        IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo.
        Breast Cancer Res Treat. 2010; 122: 359-369
        • Xu Y.
        • Zhang M.
        • Ramos C.A.
        • et al.
        Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15.
        Blood. 2014; 123: 3750-3759
        • Gomez-Eerland R.
        • Nuijen B.
        • Heemskerk B.
        • et al.
        Manufacture of gene-modified human T-cells with a memory stem/central memory phenotype.
        Hum Gene Ther Methods. 2014; 25: 277-287
        • Gargett T.
        • Brown M.P.
        Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2.
        Cytotherapy. 2015; 17: 487-495
        • 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
        • Younan P.M.
        • Polacino P.
        • Kowalski J.P.
        • et al.
        Positive selection of mC46-expressing CD4+ T cells and maintenance of virus specific immunity in a primate AIDS model.
        Blood. 2013; 122: 179-187
        • Chan D.C.
        • Chutkowski C.T.
        • Kim P.S.
        Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target.
        Proc Natl Acad Sci U S A. 1998; 95: 15613-15617
        • Leslie G.J.
        • Wang J.
        • Richardson M.W.
        • et al.
        Potent and broad inhibition of HIV-1 by a peptide from the gp41 Heptad Repeat-2 domain conjugated to the CXCR4 amino terminus.
        PLoS Pathog. 2016; 12: e1005983
        • Liu L.
        • Wen M.
        • Zhu Q.
        • Kimata J.T.
        • Zhou P.
        Glycosyl phosphatidylinositol-anchored C34 peptide derived from human immunodeficiency virus type 1 Gp41 is a potent entry inhibitor.
        J Neuroimmune Pharmacol. 2016; 11: 601-610
        • Malbec M.
        • Porrot F.
        • Rua R.
        • et al.
        Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission.
        J Exp Med. 2013; 210: 2813-2821
        • Wen M.
        • Arora R.
        • Wang H.
        • Liu L.
        • Kimata J.T.
        • Zhou P.
        GPI-anchored single chain Fv–an effective way to capture transiently-exposed neutralization epitopes on HIV-1 envelope spike.
        Retrovirology. 2010; 7: 79
        • Ye C.
        • Wang W.
        • Cheng L.
        • et al.
        Glycosylphosphatidylinositol-anchored anti-HIV scFv efficiently protects CD4 T cells from HIV-1 infection and deletion in hu-PBL mice.
        J Virol. 2017; 91: e01389-16
        • 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: 808-816
        • 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: 839-847
        • Anderson J.
        • Akkina R.
        HIV-1 resistance conferred by siRNA cosuppression of CXCR4 and CCR5 coreceptors by a bispecific lentiviral vector.
        AIDS Res Ther. 2005; 2: 1
        • Anderson J.
        • Akkina R.
        Complete knockdown of CCR5 by lentiviral vector-expressed siRNAs and protection of transgenic macrophages against HIV-1 infection.
        Gene Ther. 2007; 14: 1287-1297
        • Anderson J.
        • Akkina R.
        CXCR4 and CCR5 shRNA transgenic CD34+ cell derived macrophages are functionally normal and resist HIV-1 infection.
        Retrovirology. 2005; 2: 53
        • Anderson J.S.
        • Walker J.
        • Nolta J.A.
        • Bauer G.
        Specific transduction of HIV-susceptible cells for CCR5 knockdown and resistance to HIV infection: a novel method for targeted gene therapy and intracellular immunization.
        J Acquir Immune Defic Syndr. 2009; 52: 152-161
        • Butticaz C.
        • Ciuffi A.
        • Munoz 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: 373-377
        • 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: 370-376
        • Ringpis G.E.
        • Shimizu S.
        • Arokium H.
        • et al.
        Engineering HIV-1-resistant T-cells from short-hairpin RNA-expressing hematopoietic stem/progenitor cells in humanized BLT mice.
        PLoS One. 2012; 7: e53492
        • 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: 1534-1544
        • Shimizu S.
        • Ringpis G.E.
        • Marsden M.D.
        • et al.
        Rnai-mediated CCR5 knockdown provides HIV-1 resistance to memory T cells in humanized BLT mice.
        Mol Ther Nucleic Acids. 2015; 4: e227
        • An D.S.
        • Qin F.X.
        • Auyeung V.C.
        • et al.
        Optimization and functional effects of stable short hairpin RNA expression in primary human lymphocytes via lentiviral vectors.
        Mol Ther. 2006; 14: 494-504
        • Qin X.F.
        • An D.S.
        • Chen I.S.
        • Baltimore D.
        Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5.
        Proc Natl Acad Sci U S A. 2003; 100: 183-188
        • An D.S.
        • Donahue R.E.
        • Kamata M.
        • et al.
        Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates.
        Proc Natl Acad Sci U S A. 2007; 104: 13110-13115
        • Wolstein O.
        • Boyd M.
        • Millington M.
        • et al.
        Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor.
        Mol Ther Methods Clin Dev. 2014; 1: 11
        • Burke B.P.
        • Levin B.R.
        • Zhang J.
        • et al.
        Engineering cellular resistance to HIV-1 infection in vivo using a dual therapeutic lentiviral vector.
        Mol Ther Nucleic Acids. 2015; 4: e236
        • Li C.
        • Guan X.
        • Du T.
        • et al.
        Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9.
        J Gen Virol. 2015; 96: 2381-2393
        • Saayman S.
        • Ali S.A.
        • Morris K.V.
        • Weinberg M.S.
        The therapeutic application of CRISPR/Cas9 technologies for HIV.
        Expert Opin Biol Ther. 2015; 15: 819-830
        • Wang W.
        • Ye C.
        • Liu J.
        • Zhang D.
        • Kimata J.T.
        • Zhou P.
        CCR5 gene disruption via lentiviral vectors expressing Cas9 and single guided RNA renders cells resistant to HIV-1 infection.
        PLoS One. 2014; 9: e115987
        • Kang H.
        • Minder P.
        • Park M.A.
        • Mesquitta W.T.
        • Torbett B.E.
        • Slukvin I.I.
        CCR5 disruption in induced pluripotent stem cells using CRISPR/Cas9 provides selective resistance of immune cells to CCR5-tropic HIV-1 virus.
        Mol Ther Nucleic Acids. 2015; 4: e268
        • Cradick T.J.
        • Fine E.J.
        • Antico C.J.
        • Bao G.
        CRISPR/Cas9 systems targeting beta-globin and CCR5 genes have substantial off-target activity.
        Nucleic Acids Res. 2013; 41: 9584-9592
        • Liu 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: 6685-6694
        • Dey B.
        • Castillo C.S.D.
        • Berger E.A.
        Neutralization of human immunodeficiency virus type 1 by sCD4-17b, a single-chain chimeric protein, based on sequential interaction of gp120 with CD4 and coreceptor.
        J Virol. 2003; 77: 2859-2865
        • Lagenaur L.A.
        • Villarroel V.A.
        • Bundoc V.
        • Dey B.
        • Berger E.A.
        sCD4-17b bifunctional protein: Extremely broad and potent neutralization of HIV-1 Env pseudotyped viruses from genetically diverse primary isolates.
        Retrovirology. 2010; 7: 11
        • Ali A.
        • Kitchen S.G.
        • Chen I.S.
        • Ng H.L.
        • Zack J.A.
        • Yang O.O.
        HIV-1-Specific chimeric antigen receptors based on broadly neutralizing antibodies.
        J Virol. 2016; 90: 6999-7006
        • Liu B.
        • Zou F.
        • Lu L.
        • et al.
        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. 2016; 90: 9712-9724
        • Hale M.
        • Mesojednik T.
        • Romano Ibarra G.S.
        • et al.
        Engineering HIV-resistant, anti-HIV chimeric antigen receptor T cells.
        Mol Ther. 2017; 25: 570-579
        • Zhang Z.
        • Li S.
        • Gu Y.
        • Xia N.
        Antiviral therapy by HIV-1 broadly neutralizing and inhibitory antibodies.
        Int J Mol Sci. 2016; 17
        • Kwong P.D.
        • Mascola J.R.
        • Nabel G.J.
        Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning.
        Nat Rev Immunol. 2013; 13: 693-701
        • Stephenson K.E.
        • Barouch D.H.
        Broadly neutralizing antibodies for HIV eradication.
        Curr HIV/AIDS Rep. 2016; 13: 31-37
        • Guo D.
        • Shi X.
        • Arledge K.C.
        • et al.
        A single residue within the V5 region of HIV-1 envelope facilitates viral escape from the broadly neutralizing monoclonal antibody VRC01.
        J Biol Chem. 2012; 287: 43170-43179
        • Moore P.L.
        • Sheward D.
        • Nonyane M.
        • et al.
        Multiple pathways of escape from HIV broadly cross-neutralizing V2-dependent antibodies.
        J Virol. 2013; 87: 4882-4894
        • Lynch R.M.
        • Wong P.
        • Tran L.
        • et al.
        HIV-1 fitness cost associated with escape from the VRC01 class of CD4 binding site neutralizing antibodies.
        J Virol. 2015; 89: 4201-4213
        • Moore P.L.
        • Gray E.S.
        • Wibmer C.K.
        • et al.
        Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape.
        Nat Med. 2012; 18: 1688-1692
        • Vatakis D.N.
        • Koya R.C.
        • Nixon C.C.
        • et al.
        Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells.
        Proc Natl Acad Sci U S A. 2011; 108: E1408-E1416
        • Vatakis D.N.
        • Arumugam B.
        • Kim S.G.
        • Bristol G.
        • Yang O.
        • Zack J.A.
        Introduction of exogenous T-cell receptors into human hematopoietic progenitors results in exclusion of endogenous T-cell receptor expression.
        Mol Ther. 2013; 21: 1055-1063
        • Zhen A.
        • Kitchen S.
        Stem-cell-based gene therapy for HIV infection.
        Viruses. 2013; 6: 1-12
        • Bendle G.M.
        • Linnemann C.
        • Hooijkaas A.I.
        • et al.
        Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy.
        Nat Med. 2010; 16 (1p following 70): 565-570
        • Dotti G.
        • Gottschalk S.
        • Savoldo B.
        • Brenner M.K.
        Design and development of therapies using chimeric antigen receptor-expressing T cells.
        Immunol Rev. 2014; 257: 107-126
        • John L.B.
        • Devaud C.
        • Duong C.P.
        • et al.
        Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells.
        Clin Cancer Res. 2013; 19: 5636-5646
        • Xu X.J.
        • Song D.G.
        • Poussin M.
        • et al.
        Multiparameter comparative analysis reveals differential impacts of various cytokines on CART cell phenotype and function ex vivo and in vivo.
        Oncotarget. 2016; 7: 82354-82368
        • Milone M.C.
        • Fish J.D.
        • Carpenito C.
        • et al.
        Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo.
        Mol Ther. 2009; 17: 1453-1464
        • Carpenito C.
        • Milone M.C.
        • Hassan R.
        • et al.
        Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains.
        Proc Natl Acad Sci U S A. 2009; 106: 3360-3365
        • Pauken K.E.
        • Wherry E.J.
        Overcoming T cell exhaustion in infection and cancer.
        Trends Immunol. 2015; 36: 265-276
        • Day C.L.
        • Kaufmann D.E.
        • Kiepiela P.
        • et al.
        PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
        Nature. 2006; 443: 350-354
        • Cherkassky L.
        • Morello A.
        • Villena-Vargas J.
        • et al.
        Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.
        J Clin Invest. 2016; 126: 3130-3144
        • Palmer B.E.
        • Neff C.P.
        • Lecureux J.
        • et al.
        In vivo blockade of the PD-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice.
        J Immunol. 2013; 190: 211-219
        • Seung E.
        • Dudek T.E.
        • Allen T.M.
        • Freeman G.J.
        • Luster A.D.
        • Tager A.M.
        PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads.
        PLoS One. 2013; 8: e77780
        • Eichbaum Q.
        PD-1 signaling in HIV and chronic viral infection–potential for therapeutic intervention?.
        Curr Med Chem. 2011; 18: 3971-3980
        • Trautmann L.
        • Janbazian L.
        • Chomont N.
        • et al.
        Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.
        Nat Med. 2006; 12: 1198-1202
        • Chew G.M.
        • Fujita T.
        • Webb G.M.
        • et al.
        TIGIT Marks exhausted T cells, correlates with disease progression, and serves as a target for immune restoration in HIV and SIV infection.
        PLoS Pathog. 2016; 12: e1005349
        • Fujita T.
        • Burwitz B.J.
        • Chew G.M.
        • et al.
        Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques.
        J Immunol. 2014; 193: 5576-5583
        • Hoffmann M.
        • Pantazis N.
        • Martin G.E.
        • et al.
        Exhaustion of activated CD8 T cells predicts disease progression in primary HIV-1 infection.
        PLoS Pathog. 2016; 12: e1005661
        • Tian X.
        • Zhang A.
        • Qiu C.
        • et al.
        The upregulation of LAG-3 on T cells defines a subpopulation with functional exhaustion and correlates with disease progression in HIV-infected subjects.
        J Immunol. 2015; 194: 3873-3882
        • Moeller M.
        • Kershaw M.H.
        • Cameron R.
        • et al.
        Sustained antigen-specific antitumor recall response mediated by gene-modified CD4+ T helper-1 and CD8+ T cells.
        Cancer Res. 2007; 67: 11428-11437
        • Gyobu H.
        • Tsuji T.
        • Suzuki Y.
        • et al.
        Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor.
        Cancer Res. 2004; 64: 1490-1495
        • Hunziker L.
        • Klenerman P.
        • Zinkernagel R.M.
        • Ehl S.
        Exhaustion of cytotoxic T cells during adoptive immunotherapy of virus carrier mice can be prevented by B cells or CD4+ T cells.
        Eur J Immunol. 2002; 32: 374-382
        • Tishon A.
        • Lewicki H.
        • Rall G.
        • Von Herrath M.
        • Oldstone M.B.
        An essential role for type 1 interferon-gamma in terminating persistent viral infection.
        Virology. 1995; 212: 244-250
        • Snell L.M.
        Overcoming CD4 Th1 cell fate restrictions to sustain antiviral CD8 T cells and control persistent virus infection.
        Cell Rep. 2016; 16: 3286-3296
        • Sommermeyer D.
        • Hudecek M.
        • Kosasih P.L.
        • et al.
        Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo.
        Leukemia. 2016; 30: 492-500
        • Turtle C.J.
        • Hanafi L.A.
        • Berger C.
        • et al.
        CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients.
        J Clin Invest. 2016; 126: 2123-2138
        • Kimata J.T.
        • Rice A.P.
        • Wang J.
        Challenges and strategies for the eradication of the HIV reservoir.
        Curr Opin Immunol. 2016; 42: 65-70
        • Ao Z.
        • Zhu R.
        • Tan X.
        • et al.
        Activation of HIV-1 expression in latently infected CD4+ T cells by the small molecule PKC412.
        Virol J. 2016; 13: 177
        • Kovochich M.
        • Marsden M.D.
        • Zack J.A.
        Activation of latent HIV using drug-loaded nanoparticles.
        PLoS One. 2011; 6: e18270