Gene therapy's entrance into clinical settings has made it an ever more attractive field of study for various diseases. However, relatively little progress has been made in targeting kidney diseases due to poor gene delivery efficiency in renal cells. The development of novel gene therapy vectors for medical intervention to treat kidney diseases is needed. In this study, we designed and produced a pseudotyped lentiviral vector with envelope glycoproteins of Zika virus (ZIKV), and evaluated its potential use in viral vector entry, neutralization assay, and gene delivery especially in the renal context. The lentiviral vector, simplified as ZIKV-E, is pseudotyped with Env/G-TC representing the transmembrane (TM) and cytoplasmic (CY) domains of Env replaced with the TM and CY domains of the glycoprotein (G) of the vesicular stomatitis virus. In vivo results show that ZIKV-E induced efficient transduction in tubular epithelial cells in mouse kidneys, demonstrating >100-fold higher expression of exogenous green fluorescent protein gene compared with that achieved by vesicular stomatitis virus G (VSV-G) protein pseudotyped lentiviral vector. The results also showed that the vector ZIKV-E transduced cells in a pH-independent manner and the transduction was inhibited by anti-ZIKV Env domain III antibodies. Results also show that ZIKV-E can be used as a surrogate for studies of ZIKV entry mechanisms and neutralization antibody assay. In all, this study successfully demonstrated a novel pseudotyped lentiviral vector ZIKV-E for inducing high transduction efficiency in renal tubular epithelial cells that could serve as a foundation for gene therapy for the treatment of inherited renal diseases in humans.
Get full access to this article
View all access options for this article.
References
1.
LiuJ, ChenJ, ZhongY, et al.OSMRbeta mutants enhance basal keratinocyte differentiation via inactivation of the STAT5/KLF7 axis in PLCA patients. Protein Cell, 2021; 12(8):653–661; doi: 10.1007/s13238-020-00818-3.
2.
VairyS, GarciaJL, TeiraP, et al.CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. Drug Des Devel Ther, 2018; 12:3885–3898; doi: 10.2147/DDDT.S138765.
3.
RodriguesGA, ShalaevE, KaramiTK, et al. Pharmaceutical development of AAV-based gene therapy products for the eye. Pharm Res, 2018; 36(2):29; doi: 10.1007/s11095-018-2554-7.
4.
JainMD, BachmeierCA, PhuocVH, et al.Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma. Ther Clin Risk Manag, 2018; 14:1007–1017; doi: 10.2147/TCRM.S145039.
5.
DavisL, ParkF. Gene therapy research for kidney diseases. Physiol Genomics, 2019; 51(9):449–461; doi: 10.1152/physiolgenomics.00052.2019.
6.
IkedaY, SunZ, RuX, et al.Efficient gene transfer to kidney mesenchymal cells using a synthetic adeno-associated viral vector. J Am Soc Nephrol, 2018; 29(9):2287–2297; doi: 10.1681/ASN.2018040426.
7.
SudaY, FukushiS, TaniH, et al.Analysis of the entry mechanism of Crimean-Congo hemorrhagic fever virus, using a vesicular stomatitis virus pseudotyping system. Arch Virol, 2016; 161(6):1447–1454; doi: 10.1007/s00705-016-2803-1.
8.
HaidS, GretheC, BankwitzD, et al.Identification of a human respiratory syncytial virus cell entry inhibitor by using a novel lentiviral pseudotype system. J Virol, 2015; 90(6):3065–3073; doi: 10.1128/JVI.03074-15.
9.
KlintworthA, NoldenT, WesthausS, et al.Cationic amphiphilic drugs enhance entry of lentiviral particles pseudotyped with rabies virus glycoprotein into non-neuronal cells. Antiviral Res, 2015; 124:122–131; doi: 10.1016/j.antiviral.2015.10.017.
10.
TaniH, IhaK, ShimojimaM, et al.Analysis of Lujo virus cell entry using pseudotype vesicular stomatitis virus. J Virol, 2014; 88(13):7317–7330; doi: 10.1128/JVI.00512-14.
11.
Paneth Iheozor-EjioforR, LevanovL, HepojokiJ, et al.Vaccinia virus-free rescue of fluorescent replication-defective vesicular stomatitis virus and pseudotyping with Puumala virus glycoproteins for use in neutralization tests. J Gen Virol, 2016; 97(5):1052–1059; doi: 10.1099/jgv.0.000437.
12.
GarroneP, FluckigerAC, MangeotPE, et al. A prime-boost strategy using virus-like particles pseudotyped for HCV proteins triggers broadly neutralizing antibodies in macaques. Sci Transl Med, 2011; 3(94):94ra71; doi: 10.1126/scitranslmed.3002330.
13.
MoeschlerS, LocherS, ConzelmannKK, et al. Quantification of Lyssavirus-neutralizing antibodies using vesicular stomatitis virus pseudotype particles. Viruses, 2016; 8(9); doi: 10.3390/v8090254.
14.
PleckaityteM, BremerCM, GedvilaiteA, et al. Construction of polyomavirus-derived pseudotype virus-like particles displaying a functionally active neutralizing antibody against hepatitis B virus surface antigen. BMC Biotechnol, 2015; 15:85; doi: 10.1186/s12896-015-0203-3.
15.
FroelichS, TaiA, KennedyK, et al.Pseudotyping lentiviral vectors with aura virus envelope glycoproteins for DC-SIGN-mediated transduction of dendritic cells. Hum Gene Ther, 2011; 22(10):1281–1291; doi: 10.1089/hum.2010.196.
16.
HumbertJM, FrechaC, Amirache BouafiaF, et al.Measles virus glycoprotein-pseudotyped lentiviral vectors are highly superior to vesicular stomatitis virus G pseudotypes for genetic modification of monocyte-derived dendritic cells. J Virol, 2012; 86(9):5192–5203; doi: 10.1128/JVI.06283-11.
17.
BeckS, HenssL, WeidnerT, et al.Identification of entry inhibitors of Ebola virus pseudotyped vectors from a myxobacterial compound library. Antiviral Res, 2016; 132:85–91; doi: 10.1016/j.antiviral.2016.05.017.
18.
ShahPP, WangT, KaletskyRL, et al.A small-molecule oxocarbazate inhibitor of human cathepsin L blocks severe acute respiratory syndrome and ebola pseudotype virus infection into human embryonic kidney 293T cells. Mol Pharmacol, 2010; 78(2):319–324; doi: 10.1124/mol.110.064261.
19.
ChanE, Heilek-SnyderG, CammackN, et al.Development of a Moloney murine leukemia virus-based pseudotype anti-HIV assay suitable for accurate and rapid evaluation of HIV entry inhibitors. J Biomol Screen, 2006; 11(6):652–663; doi: 10.1177/1087057106288881.
20.
EvginL, IlkowCS, Bourgeois-DaigneaultMC, et al. Complement inhibition enables tumor delivery of LCMV glycoprotein pseudotyped viruses in the presence of antiviral antibodies. Mol Ther Oncolytics, 2016; 3:16027; doi: 10.1038/mto.2016.27.
21.
PowellTJ, SilkJD, SharpsJ, et al.Pseudotyped influenza A virus as a vaccine for the induction of heterotypic immunity. J Virol, 2012; 86(24):13397–13406; doi: 10.1128/JVI.01820-12.
22.
ToberR, BankiZ, EgererL, et al.VSV-GP: A potent viral vaccine vector that boosts the immune response upon repeated applications. J Virol, 2014; 88(9):4897–4907; doi: 10.1128/JVI.03276-13.
23.
L C McGuiganVS, RoosJM, PayneLG. Recombinant-expressed virus-like particle pseudotypes as an approach to vaccine development. Vaccine, 1993; 11(6):675–678; doi: 10.1016/0264-410x(93)90316-p.
24.
LoganN, DundonWG, DialloA, et al.Enhanced immunosurveillance for animal morbilliviruses using vesicular stomatitis virus (VSV) pseudotypes. Vaccine, 2016; 34(47):5736–5743; doi: 10.1016/j.vaccine.2016.10.010.
25.
LennemannNJ, HerbertAS, BrouilletteR, et al. Vesicular stomatitis virus pseudotyped with Ebola virus glycoprotein serves as a protective, noninfectious vaccine against Ebola virus challenge in mice. J Virol, 2017; 91(17); doi: 10.1128/JVI.00479-17.
26.
MatassovD, MarziA, LathamT, et al.Vaccination with a highly attenuated recombinant vesicular stomatitis virus vector protects against challenge with a lethal dose of Ebola virus. J Infect Dis, 2015; 212Suppl 2:S443–S451; doi: 10.1093/infdis/jiv316.
27.
PetersenLR, JamiesonDJ, PowersAM, et al.Zika virus. N Engl J Med, 2016; 374(16):1552–1563; doi: 10.1056/NEJMra1602113.
28.
BhardwajU, PandeyN, RastogiM, et al.Gist of Zika Virus pathogenesis. Virology, 2021; 560:86–95; doi: 10.1016/j.virol.2021.04.008.
29.
Cao-LormeauVM, BlakeA, MonsS, et al.Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study. Lancet, 2016; 387(10027):1531–1539; doi: 10.1016/S0140-6736(16)00562-6.
30.
LiuT, TangL, TangH, et al. Zika virus infection induces acute kidney injury through activating NLRP3 inflammasome via suppressing Bcl-2. Front Immunol, 2019; 10:1925; doi: 10.3389/fimmu.2019.01925.
31.
FariaNR, AzevedoR, KraemerMUG, et al.Zika virus in the Americas: Early epidemiological and genetic findings. Science, 2016; 352(6283):345–349; doi: 10.1126/science.aaf5036.
32.
LiuJ, WanP, LiQ, et al.Construction and identification of recombinant HEK293T cell lines expressing non-structural protein 1 of Zika virus. Int J Med Sci, 2017; 14(11):1072–1079; doi: 10.7150/ijms.20417.
33.
MaoY, YanR, LiA, et al.Lentiviral vectors mediate long-term and high efficiency transgene expression in HEK 293T cells. Int J Med Sci, 2015; 12(5):407–415; doi: 10.7150/ijms.11270.
34.
PeiN, WanR, ChenX, et al.Angiotensin-(1–7) decreases cell growth and angiogenesis of human nasopharyngeal carcinoma xenografts. Mol Cancer Ther, 2016; 15(1):37–47; doi: 10.1158/1535-7163.MCT-14-0981.
35.
ChenX, ChenS, PeiN, et al.AAV-Mediated angiotensin 1–7 overexpression inhibits tumor growth of lung cancer in vitro and in vivo. Oncotarget, 2017; 8(1):354–363; doi: 10.18632/oncotarget.13396.
36.
CarpentierDC, VevisK, TrabalzaA, et al.Enhanced pseudotyping efficiency of HIV-1 lentiviral vectors by a rabies/vesicular stomatitis virus chimeric envelope glycoprotein. Gene Ther, 2012; 19(7):761–774; doi: 10.1038/gt.2011.124.
37.
GiroglouT, CinatlJJr., RabenauH, et al.Retroviral vectors pseudotyped with severe acute respiratory syndrome coronavirus S protein. J Virol, 2004; 78(17):9007–9015; doi: 10.1128/JVI.78.17.9007-9015.2004.
38.
VanciniR, KramerLD, RibeiroM, et al.Flavivirus infection from mosquitoes in vitro reveals cell entry at the plasma membrane. Virology, 2013; 435(2):406–414; doi: 10.1016/j.virol.2012.10.013.
Cruz-OliveiraC, FreireJM, ConceicaoTM, et al.Receptors and routes of dengue virus entry into the host cells. FEMS Microbiol Rev, 2015; 39(2):155–170; doi: 10.1093/femsre/fuu004.
41.
SmitJM, MoeskerB, Rodenhuis-ZybertI, et al.Flavivirus cell entry and membrane fusion. Viruses, 2011; 3(2):160–171; doi: 10.3390/v3020160.
42.
McClureMO, SommerfeltMA, MarshM, et al.The pH independence of mammalian retrovirus infection. J Gen Virol, 1990; 71 (Pt 4):767–773; doi: 10.1099/0022-1317-71-4-767.
43.
KatenLJ, JanuszeskiMM, AndersonWF, et al.Infectious entry by amphotropic as well as ecotropic murine leukemia viruses occurs through an endocytic pathway. J Virol, 2001; 75(11):5018–5026; doi: 10.1128/JVI.75.11.5018-5026.2001.
44.
ChuaAJ, VituretC, TanML, et al. A novel platform for virus-like particle-display of flaviviral envelope domain III: Induction of Dengue and West Nile virus neutralizing antibodies. Virol J, 2013; 10:129; doi: 10.1186/1743-422X-10-129.
45.
HuHP, HsiehSC, KingCC, et al.Characterization of retrovirus-based reporter viruses pseudotyped with the precursor membrane and envelope glycoproteins of four serotypes of dengue viruses. Virology, 2007; 368(2):376–387; doi: 10.1016/j.virol.2007.06.026.
46.
RubinJD, NguyenTV, AllenKL, et al.Comparison of gene delivery to the kidney by adenovirus, adeno-associated virus, and lentiviral vectors after intravenous and direct kidney injections. Hum Gene Ther, 2019; 30(12):1559–1571; doi: 10.1089/hum.2019.127.
47.
AgrelliA, de MouraRR, CrovellaS, et al.ZIKA virus entry mechanisms in human cells. Infect Genet Evol, 2019; 69:22–29; doi: 10.1016/j.meegid.2019.01.018.
RegadasVC, SilvaMCE, AbudLG, et al.Microcephaly caused by congenital Zika virus infection and viral detection in maternal urine during pregnancy. Rev Assoc Med Bras (1992), 2018; 64(1):11–14; doi: 10.1590/1806-9282.64.01.11.
50.
GourinatAC, O'ConnorO, CalvezE, et al.Detection of Zika virus in urine. Emerg Infect Dis, 2015; 21(1):84–86, doi: 10.3201/eid2101.140894
51.
Interim Guidance for Zika Virus Testing of Urine—UnitedStates, 2016. MMWR Morb Mortal Wkly Rep, 2016; 65(18):474; doi: 10.15585/mmwr.mm6518e1.
52.
ChenJ, YangYF, ChenJ, et al. Zika virus infects renal proximal tubular epithelial cells with prolonged persistency and cytopathic effects. Emerg Microbes Infect, 2017; 6(8):e77; doi: 10.1038/emi.2017.67.
53.
ZharkikhL, ZhuX, StricklettPK, et al.Renal principal cell-specific expression of green fluorescent protein in transgenic mice. Am J Physiol Renal Physiol, 2002; 283(6):F1351–F1364; doi: 10.1152/ajprenal.0224.2001.
54.
IgarashiP, WhyteDA, LiK, et al.Cloning and kidney cell-specific activity of the promoter of the murine renal Na-K-C1 cotransporter gene. J Biol Chem, 1996; 271(16):9666–9674; doi: 10.1074/jbc.271.16.9666.
55.
WangY, RajalaA, CaoB, et al.Cell-specific promoters enable lipid-based nanoparticles to deliver genes to specific cells of the retina in vivo. Theranostics, 2016; 6(10):1514–1527; doi: 10.7150/thno.15230.
56.
KretschmerM, KadlubowskaP, HoffmannD, et al. Zikavirus pr ME envelope pseudotyped human immunodeficiency virus type-1 as a novel tool for glioblastoma-directed virotherapy. Cancers (Basel), 2020; 12(4):1000; doi: 10.3390/cancers12041000.
57.
Ruiz-JiménezF, Pérez-OlaisJH, RaymondC, et al. Challenges on the development of a pseudotyping assay for Zika glycoproteins. J Med Microbiol, 2021; 70(9):001413; doi: 10.1099/jmm.0.001413.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
