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Targeted shock-and-kill HIV-1 gene therapy approach combining CRISPR activation, suicide gene tBid and retargeted adenovirus delivery – Gene Therapy

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  • Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci. 1997;94:13193–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997;278:1291–5.

    Article  CAS  PubMed  Google Scholar 

  • Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278:1295–300.

    Article  CAS  PubMed  Google Scholar 

  • Davey RT Jr., Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci. 1999;96:15109–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palella FJ Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853–60.

    Article  PubMed  Google Scholar 

  • Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, Degen O, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019;393:2428–38.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gueler A, Moser A, Calmy A, Günthard HF, Bernasconi E, Furrer H, et al. Life expectancy in HIV-positive persons in Switzerland: matched comparison with general population. AIDS. 2017;31:427–36.

    Article  PubMed  Google Scholar 

  • Sengupta S, Siliciano RF. Targeting the Latent Reservoir for HIV-1. Immunity. 2018;48:872–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodari A, Darcis G, Lint CMV. The Current Status of Latency Reversing Agents for HIV-1 Remission. Annu Rev Virol. 2021;8:491–514.

    Article  PubMed  Google Scholar 

  • Darcis G, Das AT, Berkhout B. Tackling HIV Persistence: Pharmacological versus CRISPR-Based Shock Strategies. Viruses. 2018;10:1–17.

  • Tsai A, Irrinki A, Kaur J, Cihlar T, Kukolj G, Sloan DD, et al. Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy. J Virol. 2017;91:e02166–02116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klinnert S, Chemnitzer A, Rusert P, Metzner KJ. Systematic HIV-1 promoter targeting with CRISPR/dCas9-VPR reveals optimal region for activation of the latent provirus. J Gen Virol. 2022;103:1–10.

  • Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36:491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang SH, Ren Y, Thomas AS, Chan D, Mueller S, Ward AR, et al. Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells. J Clin Investig. 2018;128:876–89.

    Article  PubMed  PubMed Central  Google Scholar 

  • Badley AD, Sainski A, Wightman F, Lewin SR. Altering cell death pathways as an approach to cure HIV infection. Cell Death Dis. 2013;4:e718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saeb S, Assche JV, Loustau T, Rohr O, Wallet C, Schwartz C. Suicide gene therapy in cancer and HIV-1 infection: An alternative to conventional treatments. Biochem Pharmacol. 2022;197:114893.

    Article  CAS  PubMed  Google Scholar 

  • Huelsmann PM, Hofmann AD, Knoepfel SA, Popp J, Rauch P, Di Giallonardo F, et al. A suicide gene approach using the human pro-apoptotic protein tBid inhibits HIV-1 replication. BMC Biotechnol. 2011;11:1–11.

  • Dreier B, Honegger A, Hess C, Nagy-Davidescu G, Mittl PR, Grutter MG, et al. Development of a generic adenovirus delivery system based on structure-guided design of bispecific trimeric DARPin adapters. Proc Natl Acad Sci. 2013;110:E869–877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freitag PC, Brandl F, Brücher D, Weiss F, Dreier B, Plückthun A. Modular Adapters Utilizing Binders of Different Molecular Types Expand Cell-Targeting Options for Adenovirus Gene Delivery. Bioconjug Chem. 2022;33:1595–601.

    Article  CAS  PubMed  Google Scholar 

  • Freitag PC, Kaulfuss M, Flühler L, Mietz J, Weiss F, Brücher D, et al. Targeted adenovirus-mediated transduction of human T cells in vitro and in vivo. Molecular Therapy – Methods & Clinical Development. 2023;29:120–32.

    Article  CAS  Google Scholar 

  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 1998;94:481–90.

    Article  CAS  PubMed  Google Scholar 

  • Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94:491–501.

    Article  CAS  PubMed  Google Scholar 

  • Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C, Kroemer G. Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 2006;13:1423–33.

    Article  CAS  PubMed  Google Scholar 

  • Madesh M, Antonsson B, Srinivasula SM, Alnemri ES, Hajnóczky G. Rapid kinetics of tBid-induced cytochrome c and Smac/DIABLO release and mitochondrial depolarization. J Biol Chem. 2002;277:5651–9.

    Article  CAS  PubMed  Google Scholar 

  • Jordan A, Bisgrove D, Verdin E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO. 2003;22:1868–77.

    Article  CAS  Google Scholar 

  • Zhang Y, Yin C, Zhang T, Li F, Yang W, Kaminski R, et al. CRISPR/gRNA-directed synergistic activation mediator (SAM) induces specific, persistent and robust reactivation of the HIV-1 latent reservoirs. Scientific Rep. 2015;5:1–14.

  • Limsirichai P, Gaj T, Schaffer DV. CRISPR-mediated Activation of Latent HIV-1 Expression. Mol Ther. 2016;24:499–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saayman SM, Lazar DC, Scott TA, Hart JR, Takahashi M, Burnett JC, et al. Potent and Targeted Activation of Latent HIV-1 Using the CRISPR/dCas9 Activator Complex. Mol Ther. 2016;24:488–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji H, Jiang Z, Lu P, Ma L, Li C, Pan H, et al. Specific Reactivation of Latent HIV-1 by dCas9-SunTag-VP64-mediated Guide RNA Targeting the HIV-1 Promoter. Mol Ther. 2016;24:508–21.

    Article  PubMed  PubMed Central  Google Scholar 

  • Symons J, Chopra A, Malatinkova E, De Spiegelaere W, Leary S, Cooper D, et al. HIV integration sites in latently infected cell lines: evidence of ongoing replication. Retrovirology. 2017;14:1–11.

  • Chung CH, Mele AR, Allen AG, Costello R, Dampier W, Nonnemacher MR, et al. Integrated Human Immunodeficiency Virus Type 1 Sequence in J-Lat 10.6. Microbiol Resour Announc. 2020;9:e00179-20.

  • Spina CA, Anderson J, Archin NM, Bosque A, Chan J, Famiglietti M, et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog. 2013;9:e1003834.

    Article  PubMed  PubMed Central  Google Scholar 

  • Scott TA, O’Meally D, Grepo NA, Soemardy C, Lazar DC, Zheng Y, et al. Broadly active zinc finger protein-guided transcriptional activation of HIV-1. Mol Ther Methods Clin Dev. 2021;20:18–29.

    Article  CAS  PubMed  Google Scholar 

  • Miao J, Chen GG, Chun SY, Yun JP, Chak EC, Ho RL, et al. Adenovirus-mediated tBid overexpression results in therapeutic effects on p53-resistant hepatocellular carcinoma. Int J Cancer. 2006;119:1985–93.

    Article  CAS  PubMed  Google Scholar 

  • Kazhdan I, Long L, Montellano R, Cavazos DA, Marciniak RA. Targeted gene therapy for breast cancer with truncated Bid. Cancer Gene Ther. 2006;13:141–9.

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ. BID: a novel BH3 domain-only death agonist. Genes Dev. 1996;10:2859–69.

    Article  CAS  PubMed  Google Scholar 

  • Kim Y, Anderson JL, Lewin SR. Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV. Cell Host & Microbe. 2018;23:14–26.

    Article  CAS  Google Scholar 

  • Knott A, Drueppel L, Beyer T, Garke K, Berens C, Herrmann M, et al. An optimized conditional suicide switch using doxycycline-dependent expression of human tBid. Cancer Biol Ther. 2005;4:532–6.

    Article  CAS  PubMed  Google Scholar 

  • Konermann S, Brigham MD, Trevino AE, Joung J, Abudayyeh OO, Barcena C, et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature. 2015;517:583–8.

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Arango G, Li F, Xiao X, Putatunda R, Yu J, et al. Comprehensive off-target analysis of dCas9-SAM-mediated HIV reactivation via long noncoding RNA and mRNA profiling. BMC Med Genet. 2018;11:78.

    Google Scholar 

  • Mann JFS, Pankrac J, Klein K, McKay PF, King DFL, Gibson R, et al. A targeted reactivation of latent HIV-1 using an activator vector in patient samples from acute infection. EBioMedicine. 2020;59:102853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolff H, Hadian K, Ziegler M, Weierich C, Kramer-Hammerle S, Kleinschmidt A, et al. Analysis of the influence of subcellular localization of the HIV Rev protein on Rev-dependent gene expression by multi-fluorescence live-cell imaging. Exp Cell Res. 2006;312:443–56.

    Article  CAS  PubMed  Google Scholar 

  • Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV‑1 cure. Cell. 2013;155:540–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuniholm J, Coote C, Henderson AJ. Defective HIV-1 genomes and their potential impact on HIV pathogenesis. Retrovirology. 2022;19:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Telwatte S, Morón-López S, Aran D, Kim P, Hsieh C, Joshi S, et al. Heterogeneity in HIV and cellular transcription profiles in cell line models of latent and productive infection: implications for HIV latency. Retrovirology. 2019;16:32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mbonye U, Leskov K, Shukla M, Valadkhan S, Karn J. Biogenesis of P-TEFb in CD4+ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways. PLoS Pathog. 2021;17:e1009581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang D, Zhang F, Gao G. CRISPR-Based Therapeutic Genome Editing: Strategies and In Vivo Delivery by AAV Vectors. Cell. 2020;181:136–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herskovitz J, Hasan M, Patel M, Kevadiya BD, Gendelman HE. Pathways Toward a Functional HIV-1 Cure: Balancing Promise and Perils of CRISPR Therapy. In: Poli G, Vicenzi E, Romerio F, (eds). HIV Reservoirs: Methods and Protocols. 2022. Springer US, New York, NY. p. 429–45.

  • Boucher P, Cui X, Curiel DT. Adenoviral vectors for in vivo delivery of CRISPR-Cas gene. J Control Release. 2020;327:788–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar P, Ban HS, Kim SS, Wu H, Pearson T, Greiner DL, et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell. 2008;134:577–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol. 2005;23:709–17.

    Article  CAS  PubMed  Google Scholar 

  • Zhou Q, Uhlig KM, Muth A, Kimpel J, Lévy C, Münch RC, et al. Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors. J Immunol. 2015;195:2493–501.

    Article  CAS  PubMed  Google Scholar 

  • Schmid M, Ernst P, Honegger A, Suomalainen M, Zimmermann M, Braun L, et al. Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control. Nat Commun. 2018;9:450.

    Article  PubMed  PubMed Central  Google Scholar 

  • Brücher D, Kirchhammer N, Smith SN, Schumacher J, Schumacher N, Kolibius J, et al. iMATCH: an integrated modular assembly system for therapeutic combination high-capacity adenovirus gene therapy. Mol Ther Methods Clin Dev. 2021;20:572–86.

    Article  PubMed  PubMed Central  Google Scholar 

  • Descours B, Petitjean G, López-Zaragoza JL, Bruel T, Raffel R, Psomas C, et al. CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses. Nature. 2017;543:564–7.

    Article  CAS  PubMed  Google Scholar 

  • Darcis G, Kootstra NA, Hooibrink B, van Montfort T, Maurer I, Groen K, et al. CD32(+)CD4(+) T Cells Are Highly Enriched for HIV DNA and Can Support Transcriptional Latency. Cell Rep. 2020;30:2284–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abdel-Mohsen M, Kuri-Cervantes L, Grau-Exposito J, Spivak AM, Nell RA, Tomescu C, et al. CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells. Sci Transl Med. 2018;10:eaar6759.

  • Badia R, Ballana E, Castellví M, García-Vidal E, Pujantell M, Clotet B, et al. CD32 expression is associated to T-cell activation and is not a marker of the HIV-1 reservoir. Nat Commun. 2018;9:2739.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pérez L, Anderson J, Chipman J, Thorkelson A, Chun TW, Moir S, et al. Conflicting evidence for HIV enrichment in CD32(+) CD4 T cells. Nature. 2018;561:E9–e16.

    Article  PubMed  PubMed Central  Google Scholar 

  • Osuna CE, Lim SY, Kublin JL, Apps R, Chen E, Mota TM, et al. Evidence that CD32a does not mark the HIV-1 latent reservoir. Nature. 2018;561:E20–e28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin GE, Pace M, Thornhill JP, Phetsouphanh C, Meyerowitz J, Gossez M, et al. CD32-Expressing CD4 T cells are phenotypically diverse and can contain proviral HIV DNA. Front Immunol. 2018;9:1–13.

  • Arsentieva NA, Batsunov OK, Semenov AV, Kudryavtsev IV, Esaulenko EV, Boeva EV, et al. Association between Higher CD32a+CD4+ T Cell Count and Viral Load in the Peripheral Blood of HIV-infected Patients. Open AIDS J. 2021;15:35–41.

    Article  CAS  Google Scholar 

  • Chavez A, Scheiman J, Vora S, Pruitt BW, Tuttle M, PRI E, et al. Highly efficient Cas9-mediated transcriptional programming. Nat Methods. 2015;12:326–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perez-Pinera P, Kocak DD, Vockley CM, Adler AF, Kabadi AM, Polstein LR, et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat Methods. 2013;10:973–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss A, Wiskocil RL, Stobo JD. The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. J Immunol. 1984;133:123–8.

    Article  CAS  PubMed  Google Scholar 

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