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Review Article

Dissecting the Therapeutic Relevance of Gene Therapy in NeuroAIDS: An Evolving Epidemic

Author(s): Bushra Nabi, Saleha Rehman, Faheem Hyder Pottoo, Sanjula Baboota and Javed Ali*

Volume 20, Issue 3, 2020

Page: [174 - 183] Pages: 10

DOI: 10.2174/1566523220666200615151805

Price: $65

Abstract

NeuroAIDS, a disease incorporating both infectious and neurodegenerative pathways, is still a formidable challenge for the researchers to deal with. The primary concern for the treatment of neuroAIDS still remains the inaccessibility of the viral reservoir, making it indispensable for novel techniques to be continuously innovated. Since the brain serves as a reservoir for viral replication, it is pragmatic and a prerequisite to overcome the related barriers in order to improve the drug delivery to the brain. The current treatment ideology is based on the combinatorial approach of a mocktail of antiretroviral drugs. However, complete eradication of the disease could not be achieved. Thereby the arena of gene-based cellular delivery is trending and has created a niche for itself in the present scenario. To establish the supremacy of gene delivery, it is advisable to have a better understanding of the molecular mechanism involved in the due process. The mechanism associated with the activity of the anti-HIV gene lies in their intrinsic property to impart resistance to the HIV infection by targeting the viral entry channels. This review principally emphasizes on different types of gene therapies explored so far for the management of AIDS and its associated neurological conditions. Therefore it could rightly be said that we are at the crossroad where the need of the hour is to develop novel strategies for curbing AIDS and its associated neurological conditions.

Keywords: Gene therapy, neuroaids, provirus, CRISPR, ZFN, anti-retroviral drugs.

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[1]
Nair M, Jayant RD, Kaushik A, Sagar V. Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS. Adv Drug Deliv Rev 2016; 103: 202-17.
[http://dx.doi.org/10.1016/j.addr.2016.02.008] [PMID: 26944096]
[2]
Judge M, Parker E, Naniche D, et al. Gene expression: the key to understanding HIV-1 infection? Microbiol Mol Bio 2020; 84(2): e00080-19.
[http://dx.doi.org/10.1128/MMBR.00080-19] [PMID: 32404327]
[3]
Swamy MN, Wu H, Shankar P. Recent advances in RNAi-based strategies for therapy and prevention of HIV-1/AIDS. Adv Drug Deliv Rev 2016; 103: 174-86.
[http://dx.doi.org/10.1016/j.addr.2016.03.005] [PMID: 27013255]
[4]
Veenhuis RT, Clements JE, Gama L. HIV eradication strategies: implications for the central nervous system. Curr HIV/AIDS Rep 2019; 16(1): 96-104.
[http://dx.doi.org/10.1007/s11904-019-00428-7] [PMID: 30734905]
[5]
Wang Q, Cheng H, Peng H, Zhou H, Li PY, Langer R. Non-genetic engineering of cells for drug delivery and cell-based therapy. Adv Drug Deliv Rev 2015; 91: 125-40.
[http://dx.doi.org/10.1016/j.addr.2014.12.003] [PMID: 25543006]
[6]
Batrakova EV, Gendelman HE, Kabanov AV. Cell-mediated drug delivery. Expert Opin Drug Deliv 2011; 8(4): 415-33.
[http://dx.doi.org/10.1517/17425247.2011.559457] [PMID: 21348773]
[7]
Pottoo FH, Barkat MA. Nanotechnological based miRNA intervention in the therapeutic management of neuroblastoma Semin Cancer Biol 2019. S1044-579X(19): 30224-X..
[http://dx.doi.org/10.1016/j.semcancer.2019.09.017] [PMID: 31562954]
[8]
Cheng H, Byrska-Bishop M, Zhang CT, et al. Stem cell membrane engineering for cell rolling using peptide conjugation and tuning of cell-selectin interaction kinetics. Biomaterials 2012; 33(20): 5004-12.
[http://dx.doi.org/10.1016/j.biomaterials.2012.03.065] [PMID: 22494889]
[9]
Churchill M, Nath A. Where does HIV hide? A focus on the central nervous system. Curr Opin HIV AIDS 2013; 8(3): 165-9.
[http://dx.doi.org/10.1097/COH.0b013e32835fc601] [PMID: 23429501]
[10]
Pernet O, Yadav SS, An DS. Stem cell-based therapies for HIV/AIDS. Adv Drug Deliv Rev 2016; 103: 187-201.
[http://dx.doi.org/10.1016/j.addr.2016.04.027] [PMID: 27151309]
[11]
Khalili K, White MK, Jacobson JM. Novel AIDS therapies based on gene editing. Cell Mol Life Sci 2017; 74(13): 2439-50.
[http://dx.doi.org/10.1007/s00018-017-2479-z] [PMID: 28210784]
[12]
Gersbach CA, Perez-Pinera P. Activating human genes with zinc finger proteins, transcription activator-like effectors and CRISPR/Cas9 for gene therapy and regenerative medicine. Expert Opin Ther Targets 2014; 18(8): 835-9.
[http://dx.doi.org/10.1517/14728222.2014.913572] [PMID: 24917359]
[13]
Niu J, Zhang B, Chen H. Applications of TALENs and CRISPR/Cas9 in human cells and their potentials for gene therapy. Mol Biotechnol 2014; 56(8): 681-8.
[http://dx.doi.org/10.1007/s12033-014-9771-z] [PMID: 24870618]
[14]
Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. Gene therapy of primary T cell immunodeficiencies. Gene 2013; 525(2): 170-3.
[http://dx.doi.org/10.1016/j.gene.2013.03.092] [PMID: 23583799]
[15]
Cicalese MP, Aiuti A. Clinical applications of gene therapy for primary immunodeficiencies. Hum Gene Ther 2015; 26(4): 210-9.
[http://dx.doi.org/10.1089/hum.2015.047] [PMID: 25860576]
[16]
Allen AG, Chung CH, Atkins A, et al. Gene editing of HIV-1 co-receptors to prevent and/or cure virus infection. Front Microbiol 2018; 9: 2940.
[http://dx.doi.org/10.3389/fmicb.2018.02940] [PMID: 30619107]
[17]
Zahur M, Tolö J, Bähr M, Kügler S. Long-term assessment of AAV-mediated zinc finger nuclease expression in the mouse brain. Front Mol Neurosci 2017; 10: 142.
[http://dx.doi.org/10.3389/fnmol.2017.00142] [PMID: 28588449]
[18]
Tebas P, Stein D, Tang WW, 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.
[http://dx.doi.org/10.1056/NEJMoa1300662] [PMID: 24597865]
[19]
Kwarteng A, Ahuno ST, Kwakye-Nuako G. The therapeutic landscape of HIV-1 via genome editing. AIDS Res Ther 2017; 14(1): 32.
[http://dx.doi.org/10.1186/s12981-017-0157-8] [PMID: 28705213]
[20]
Perez EE, Wang J, Miller JC, 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.
[http://dx.doi.org/10.1038/nbt1410] [PMID: 18587387]
[21]
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(8): 839-47.
[http://dx.doi.org/10.1038/nbt.1663] [PMID: 20601939]
[22]
Khamaikawin W, Saoin S, Nangola S, et al. Combined antiviral therapy using designed molecular scaffolds targeting two distinct viral functions, HIV-1 genome integration and capsid assembly. Mol Ther Nucleic Acids 2015; 4 e249
[http://dx.doi.org/10.1038/mtna.2015.22] [PMID: 26305555]
[23]
Wiedenheft B, Sternberg SH, Doudna JA. RNA-guided genetic silencing systems in bacteria and archaea. Nature 2012; 482(7385): 331-8.
[http://dx.doi.org/10.1038/nature10886] [PMID: 22337052]
[24]
Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell 2014; 157(6): 1262-78.
[http://dx.doi.org/10.1016/j.cell.2014.05.010] [PMID: 24906146]
[25]
Koo T, Lee J, Kim JS. Measuring and reducing off-target activities of programmable nucleases including CRISPR-Cas9. Mol Cells 2015; 38(6): 475-81.
[http://dx.doi.org/10.14348/molcells.2015.0103] [PMID: 25985872]
[26]
Ueda S, Ebina H, Kanemura Y, Misawa N, Koyanagi Y. Anti-HIV-1 potency of the CRISPR/Cas9 system insufficient to fully inhibit viral replication. Microbiol Immunol 2016; 60(7): 483-96.
[http://dx.doi.org/10.1111/1348-0421.12395] [PMID: 27278725]
[27]
Liao HK, Gu Y, Diaz A, et al. Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells. Nat Commun 2015; 6: 6413.
[http://dx.doi.org/10.1038/ncomms7413] [PMID: 25752527]
[28]
Maeder ML, Gersbach CA. Genome-editing technologies for gene and cell therapy. Mol Ther 2016; 24(3): 430-46.
[http://dx.doi.org/10.1038/mt.2016.10] [PMID: 26755333]
[29]
Kaminski R, Bella R, Yin C, et al. Excision of HIV-1 DNA by gene editing: a proof-of-concept in vivo study. Gene Ther 2016; 23(8-9): 690-5.
[http://dx.doi.org/10.1038/gt.2016.41] [PMID: 27194423]
[30]
Ran FA, Cong L, Yan WX, et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 2015; 520(7546): 186-91.
[http://dx.doi.org/10.1038/nature14299] [PMID: 25830891]
[31]
Wang G, Zhao N, Berkhout B, Das AT. CRISPR-Cas based antiviral strategies against HIV-1. Virus Res 2018; 244: 321-32.
[http://dx.doi.org/10.1016/j.virusres.2017.07.020] [PMID: 28760348]
[32]
Liu 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.
[http://dx.doi.org/10.1186/s13578-017-0174-2] [PMID: 28904745]
[33]
Saayman SM, Lazar DC, Scott TA, et al. Potent and targeted activation of latent HIV-1 using the CRISPR/dCas9 activator complex. Mol Ther 2016; 24(3): 488-98.
[http://dx.doi.org/10.1038/mt.2015.202] [PMID: 26581162]
[34]
Yin C, Zhang T, Qu X, et al. In Vivo excision of HIV-1 provirus by saCas9 and multiplex single-guide RNAs in animal models. Mol Ther 2017; 25(5): 1168-86.
[http://dx.doi.org/10.1016/j.ymthe.2017.03.012] [PMID: 28366764]
[35]
Bella R, Kaminski R, Mancuso P, et al. Removal of HIV DNA by CRISPR from patient blood engrafts in humanized mice. Mol Ther Nucleic Acids 2018; 12(12): 275-82.
[http://dx.doi.org/10.1016/j.omtn.2018.05.021] [PMID: 30195766]
[36]
Hu W, Kaminski R, Yang F, et al. RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Proc Natl Acad Sci USA 2014; 111(31): 11461-6.
[http://dx.doi.org/10.1073/pnas.1405186111] [PMID: 25049410]
[37]
Cho SW, Kim S, Kim JM, Kim JS. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat Biotechnol 2013; 31(3): 230-2.
[http://dx.doi.org/10.1038/nbt.2507] [PMID: 23360966]
[38]
Mandal PK, Ferreira LMR, 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.
[http://dx.doi.org/10.1016/j.stem.2014.10.004] [PMID: 25517468]
[39]
Kim D, Bae S, Park J, et al. Digenome-seq: genome-wide profiling of CRISPR-Cas9 off-target effects in human cells. Nat Methods 2015; 12(3): 237-43.
[http://dx.doi.org/10.1038/nmeth.3284] [PMID: 25664545]
[40]
Hou P, Chen S, Wang S, et al. Genome editing of CXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection. Sci Rep 2015; 5: 15577.
[http://dx.doi.org/10.1038/srep15577] [PMID: 26481100]
[41]
Yu AQ, Ding Y, Lu ZY, et al. TALENs-mediated homozygous CCR5Δ32 mutations endow CD4+ U87 cells with resistance against HIV 1 infection. Mol Med Rep 2018; 17(1): 243-9.
[PMID: 29115572]
[42]
Khalili K, Kaminski R, Gordon J, Cosentino L, Hu W. Genome editing strategies: potential tools for eradicating HIV-1/AIDS. J Neurovirol 2015; 21(3): 310-21.
[http://dx.doi.org/10.1007/s13365-014-0308-9] [PMID: 25716921]
[43]
Shi B, Li J, Shi X, et al. TALEN mediated knockout of CCR5 confers protection against infection of human immunodeficiency virus. J Acquir Immune Defic Syndr 2017; 74(2): 229-41.
[http://dx.doi.org/10.1097/QAI.0000000000001190] [PMID: 27749600]
[44]
Zhou J, Rossi JJ. Current progress in the development of RNAi-based therapeutics for HIV-1. Gene Ther 2011; 18(12): 1134-8.
[http://dx.doi.org/10.1038/gt.2011.149] [PMID: 21956690]
[45]
Khamaikawin W, Shimizu S, Kamata M, et al. Modeling anti-HIV-1 HSPC-based gene therapy in humanized mice previously infected with HIV-1. Mol Ther Methods Clin Dev 2017; 9: 23-32.
[http://dx.doi.org/10.1016/j.omtm.2017.11.008] [PMID: 29322065]
[46]
Suzuki K, Hattori S, Marks K, et al. Promoter targeting shRNA suppresses HIV-1 infection in vivo through transcriptional gene silencing. Mol Ther Nucleic Acids 2013; 2 e137
[http://dx.doi.org/10.1038/mtna.2013.64] [PMID: 24301868]
[47]
Ringpis GE, 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(12) e53492
[http://dx.doi.org/10.1371/journal.pone.0053492] [PMID: 23300932]
[48]
Neff CP, Zhou J, Remling L, et al. An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice. Sci Transl Med 2011; 3(66): 66ra6.
[http://dx.doi.org/10.1126/scitranslmed.3001581] [PMID: 21248316]
[49]
Kim SS, 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(2): 370-6.
[http://dx.doi.org/10.1038/mt.2009.271] [PMID: 19997090]
[50]
Kumar P, Ban HS, Kim SS, et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 2008; 134(4): 577-86.
[http://dx.doi.org/10.1016/j.cell.2008.06.034] [PMID: 18691745]
[51]
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.
[http://dx.doi.org/10.1038/mtm.2013.11] [PMID: 26015947]
[52]
Shimizu S, Ringpis GE, Marsden MD, 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
[http://dx.doi.org/10.1038/mtna.2015.3] [PMID: 25689223]
[53]
Fraternale A, Casabianca A, Rossi L, et al. Erythrocytes as carriers of reduced glutathione (GSH) in the treatment of retroviral infections. J Antimicrob Chemother 2003; 52(4): 551-4.
[http://dx.doi.org/10.1093/jac/dkg428] [PMID: 12972455]
[54]
Galkina E, Ley K. Leukocyte recruitment and vascular injury in diabetic nephropathy. J Am Soc Nephrol 2006; 17(2): 368-77.
[http://dx.doi.org/10.1681/ASN.2005080859] [PMID: 16394109]
[55]
Chang YN, Guo H, Li J, et al. Adjusting the balance between effective loading and vector migration of macrophage vehicles to deliver nanoparticles. PLoS One 2013; 8(10) e76024
[http://dx.doi.org/10.1371/journal.pone.0076024] [PMID: 24116086]
[56]
Dou H, Grotepas CB, McMillan JM, et al. Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS. J Immunol 2009; 183(1): 661-9.
[http://dx.doi.org/10.4049/jimmunol.0900274] [PMID: 19535632]
[57]
Repunte-Canonigo V, Lefebvre C, George O, et al. Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats. Mol Neurodegener 2014; 9: 26.
[http://dx.doi.org/10.1186/1750-1326-9-26] [PMID: 24980976]
[58]
Hale M, Mesojednik T, Romano Ibarra GS, et al. Engineering HIV-resistant, anti-HIV chimeric antigen receptor T cells. Mol Ther 2017; 25(3): 570-9.
[http://dx.doi.org/10.1016/j.ymthe.2016.12.023] [PMID: 28143740]
[59]
Tong J, Buch S, Yao H, et al. Monocytes-derived macrophages mediated stable expression of human brain-derived neurotrophic factor, a novel therapeutic strategy for neuroAIDS. PLoS One 2014; 9(2) e82030
[http://dx.doi.org/10.1371/journal.pone.0082030] [PMID: 24505242]
[60]
Burke BP, Levin BR, 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
[http://dx.doi.org/10.1038/mtna.2015.10] [PMID: 25872029]
[61]
Cyranoski D. Replications, ridicule and a recluse: the controversy over NgAgo gene-editing intensifies. Nature 2016; 536(7615): 136-7.
[http://dx.doi.org/10.1038/536136a] [PMID: 27510204]

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