Overview of Gene Delivery into Cells Using HSV‐1‐Based Vectors

Rachael L. Neve1

1 Massachusetts Institute of Technology, Cambridge, Massachusetts
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 4.12
DOI:  10.1002/0471142301.ns0412s61
Online Posting Date:  October, 2012
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This overview describes the considerations involved in the preparation and use of a herpes simplex virus type 1 (HSV‐1) amplicon as a vector for gene transfer into neurons. Strategies for gene delivery into neurons, either to study the molecular biology of brain function or for gene therapy, must utilize vectors that persist stably in postmitotic cells and that can be targeted both spatially and temporally in the nervous system in vivo. This unit describes the biology of HSV‐1 along with a discussion covering development of amplicon and genomic HSV‐1 vectors. Advantages and disadvantages of current HSV‐1 vectors are presented, and HSV‐1 vectors are compared with other vectors for gene transfer into neurons. Curr. Protoc. Neurosci. 61:4.12.1‐4.12.7. © 2012 by John Wiley & Sons, Inc.

Keywords: viral gene transfer; HSV‐1 vectors; gene delivery into the brain

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Table of Contents

  • Biology of HSV‐1
  • Development of Amplicon and Genomic HSV‐1 Vectors
  • Advantages and Disadvantages of Present‐Day Amplicon Vectors
  • Comparison of HSV‐1 with Other Vectors for Gene Transfer Into Neurons
  • Literature Cited
  • Tables
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PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
   Bursztajn, S., DeSouza, R., McPhie, D.L., Berman, S.A., Shioi, J., Robakis, N.K., and Neve, R.L. 1998. Overexpression in neurons of human presenilin‐1 or a presenilin‐1 familial Alzheimer disease mutant does not enhance apoptosis. J. Neurosci. 18:9790‐9799.
   Byrnes, A.P., MacLaren, R.D., and Charlton, H.M. 1996. Immunological instability of persistent adenovirus vectors in the brain: Peripheral exposure to vector leads to renewed inflammation, reduced gene expression, and demyelination. J. Neurosci. 16:3045‐3055.
   Carlezon, W.A.Jr., Boundy, V.A., Haile, C.N., Kalb, R.G., Neve, R.L., and Nestler, E.J. 1997. Sensitization to morphine induced by viral‐mediated gene transfer. Science 277:812‐814.
   Choi‐Lundberg, D.L., Lin, Q., Chang, Y.‐N., Chiang, Y.L., Hay, C.M., Mohajeri, H., Davidson, B.L., and Bohn, M.C. 1997. Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275:838‐841.
   Croen, K.D., Ostrove, J.M., Dragovic, L.J., Smialek, J.E., and Straus, S.E. 1987. Latent herpes simplex virus in human trigeminal ganglia. Detection of an immediate‐early gene anti‐sense transcript by in situ hybridization. N. Engl. J. Med. 317:1422‐1432.
   During, M.J., Naegele, J.R., O'Malley, K.L., and Geller, A.I. 1994. Long‐term behavioral recovery in Parkinsonian rats by an HSV vector expressing tyrosine hydroxylase. Science 266:1399‐1403.
   Fink, D.J., DeLuca, N.A., Goins, W.F., and Glorioso, J.C. 1996. Gene transfer to neurons using herpes simplex virus‐based vectors. Annu. Rev. Neurosci. 19:265‐287.
   Fraefel, C., Song, S., Lim, F., Lang, P., Yu, L., Wang, Y., Wild, P., and Geller, A.I. 1996. Helper virus‐free transfer of herpes simplex virus type I plasmid vectors into neural cells. J. Virol. 68:7190‐7187.
   Gaffney, D.F., McLauchlin, J., Whitton, J.L., and Clements, J.B. 1985. A modular system for the assay of transcription regulatory signals: The sequence TAATGARAT is required for herpes simplex virus immediate early gene activation. Nucleic Acids Res. 13:7847‐7863.
   Gao, Q., Sun, M., Wang, X., and Geller, A.I. 2007. Isolation of an enhancer from the rat tyrosine hyddroxylase promoter that supports long‐term, neuronal‐specific expression from a neurofilament promoter, in a helper virus‐free HSV‐1 vector system. Brain Res. 1130:1‐16.
   Geller, A.I. and Breakefield, X.O. 1988. A defective HSV‐1 vector expresses Escherichia coli beta‐galactosidase in cultured peripheral neurons. Science 241:1667‐1669.
   Geller, A.I., Keyomarsi, K., Bryan, J., and Pardee, A.B. 1990. An efficient deletion mutant packaging system for defective herpes simplex virus vectors: Potential applications to human gene therapy and neuronal physiology. Proc. Natl. Acad. Sci. U.S.A. 87:8950‐8954.
   Gravel, C., Götz, R., Lorrain, A., and Sendtner, M. 1997. Adenoviral gene transfer of ciliary neurotrophic factor and brain‐derived neurotrophic factor leads to long‐term survival of axotomized motor neurons. Nat. Med. 3:765‐770.
   Haase, G., Kennel, P., Petemann, B., Vigne, E., Akli, S., Revah, F., Schmalbruch, H., and Kahn, A. 1997. Gene therapy of murine motor neurons disease using adenoviral vectors for neurotrophic factors. Nat. Med. 3:429‐436.
   Hannas‐Djebbara, Z., Bazès, M.D., Sacchettoni, S., Prod'hon, C., Jouvet, M., Belin, M.‐F., and Jacquemont, B. 1997. Transgene expression of plasmid DNAs directed by viral or neural promoters in the rat brain. Mol. Brain Res. 46:91‐99.
   Honess, R.W. and Roizman, B. 1974. Regulation of herpes virus macromolecular synthesis. I. Cascade regulation of the synthesis of three groups of viral proteins. J. Virol. 14:8‐19.
   Jin, B.K., Belloni, M., Conti, B., Federoff, H.J., Starr, R., Son, J.H., Baker, H., and Joh, T.H. 1996. Prolonged in vivo gene expression driven by a tyrosine hydroxylase promoter in a defective herpes simplex virus amplicon vector. Hum. Gene Ther. 7:2015‐2024.
   Johnson, P.A., Miyanohara, A., Levine, F., Cahill, T., and Friedmann, T. 1992. Cytotoxicity of a replication‐defective mutant of herpes simplex virus type 1. J. Virol. 66:2952‐2965.
   Kajiwara, K., Byrnes, A.P., Charlton, H.M., Wood, M.J.A., and Wood, K.J. 1997. Immune responses to adenoviral vectors during gene transfer in the brain. Hum. Gene Ther. 8:253‐265.
   Kaplitt, M.G., Leone, P., Samulski, R.J., Xiao, X., Pfaff, D.W., O'Malley, K.L., and During, M.J. 1994. Long‐term gene expression and phenotypic correction using adeno‐associated virus vectors in the mammalian brain. Nature Genet. 8:148‐154.
   Katz, J., Bodin, T., and Coen, D.M. 1990. Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication incompetent mutants. J. Virol. 64:4288‐4295.
   Latchman, D.S. 1990. Molecular biology of herpes simplex virus latency. J. Exp. Pathol. 71:133‐141.
   Lim, F., Hartley, D., Starr, P., Lang, P., Song, S., Yu, L., Wang, Y., and Geller, A.I. 1996. Generation of high‐titer defective HSV‐1 vectors using an IE 2 deletion mutant and quantitative study of expression in cultured cortical cells. BioTechniques 20:460‐469.
   Liu, M., Wang, X., and Geller, A.I. 2009. Improved long‐term expression from helper virus‐free HSV‐1 vectors packaged using combinations of mutated HSV‐1 proteins that include the UL13 protein kinase and specific components of the VP16 transcriptional complex. BMC Mol. Biol. 10:58‐69.
   Mackem, S. and Roizman, B. 1982a. Differentiation between alpha promoter and regulatory regions of herpes simplex virus type I: The functional domains and sequence of a movable alpha regulator. Proc. Natl. Acad. Sci. U.S.A. 79:4917‐4291.
   Mackem, S. and Roizman, B. 1982b. Structural features of the herpes simplex virus alpha gene 4, 0, and 27 promoter‐regulatory sequences which confer alpha regulation on chimeric thymidine kinase. J. Virol. 44:939‐949.
   Mandel, R.J., Rendahl, K.G., Spratt, S.K., Snyder, R.O., Cohen, L.K., and Leff, S.E. 1998. Characterization of intrastriatal recombinant adeno‐associated virus‐mediated gene transfer of human tyrosine hydroxylase and human GFP‐cyclohydrolase I in a rat model of Parkinson's disease. J. Neurosci. 18:4271‐4284.
   Marconi, P., Krisky, D., Oligino, T., Poliani, P.L., Ramakrishnan, R., Goins, W.F., Fink, D.J., and Glorioso, J.C. 1996. Replication‐defective herpes simplex virus vectors for gene transfer in vitro. Proc. Natl. Acad. Sci. U.S.A. 93:11319‐11320.
   Montgomery, R.I., Warner, M.S., Lum, B.J., and Spear, P.G. 1996. Herpes simplex virus‐1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87:427‐436.
   Neve, R.L. and Geller, A.I. 1996. A defective herpes simplex virus vector system for gene delivery into the brain: Comparison with alternative gene delivery systems and usefulness for gene therapy. Clin. Neurosci. 3:262‐267.
   Neve, R.L., Howe, J.R., Hong, S., and Kalb, R.G. 1997. Introduction of glutamate receptor subunit 1 into motor neurons in vivo using a recombinant herpes simplex virus alters the functional properties of AMPA receptors. Neuroscience 79:435‐447.
   Oroskar, A.A. and Read, G.S. 1989. Control of mRNA stability by the virion host shutoff function of herpes simplex virus. J. Virol. 63:1897‐1906.
   Poeschla, E.M., Wong‐Staal, F., and Looney, D.J. 1998. Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors. Nat. Med. 3:354‐357.
   Rasmussen, M., Kong, L., Zhang, G.Rl, Liu, M., Wang, X., Szabo, G., Curthoys, N.P., and Geller, A.I. 2007. Glutamatergic of GABAergic neuron‐specific, long‐term expression in neocortical neurons from helper virus‐free HSV‐1 vectors containing the phosphate‐activated glutaminase, vesicular glutamate transporter, or glutamic acid decarboxylase promoter. Brain Res. 1144:19‐32.
   Roizman, B. and Jenkins, F.J. 1985. Genetic engineering of novel genomes of large DNA viruses. Science 229:1208‐1214.
   Roizman, B. and Sears, A.E. 1990. Herpes simplex viruses and their replication. In Virology, 2nd ed. (B. Fields, D.M. Knipe, R.M. Chanock, M.S. Hirsch, J.L. Melnick, T.P. Monath, and B. Roizman, eds.) pp. 1795‐1841. Raven Press, New York.
   Spaete, R. and Frenkel, N. 1982. The herpes simplex virus amplicon: A new eukaryotic defective‐virus cloning‐amplifying vector. Cell 30:305‐310.
   Spaete, R. and Frenkel, N. 1985. The herpes simplex virus amplicon: Analyses of cis‐acting replication functions. Proc. Natl. Acad. Sci. U.S.A. 82:694‐698.
   Spear, P.G. 1993. Entry of alphaherpesviruses into cells. Semin. Virol. 4:167‐180.
   Stevens, J.G., Wagner, E.K., Devi‐Rao, G.B., Cook, M.L., and Feldman, L.T. 1987. RNA complementary to a herpes virus alpha gene mRNA is prominent in latently infected neurons. Science 235:1056‐1059.
   Stow, N. and McMonagle, E. 1982. Propagation of foreign DNA sequences linked to a herpes simplex virus origin of replication. In Eucaryotic Viral Vectors (Y. Gluzman, ed.) pp. 199‐204. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
   Tripathy, S.K., Black, H.B., Goldwasser, E., and Leiden, J.M. 1996. Immune responses to transgene‐encoded proteins limit the stability of gene expression after injection of replication‐defective adenovirus vectors. Nat. Med. 2:545‐550.
   Valyi‐Nagi, T., Deshmane, S.L., Spivack, J.G., Steiner, I., Ace, C.I., Preston, C.M., and Fraser, N.W. 1991. Investigation of herpes simplex virus type 1 (HSV‐1) gene expression and DNA synthesis during the establishment of latent infection by an HSV‐1 mutant, in 1814, that does not replicate in mouse trigeminal ganglia. J. Gen. Virol. 72:641‐649.
   Vlazny, D., Kwong, A., and Frenkel, N. 1982. Site‐specific cleavage/packaging of herpes simplex virus DNA and the selective maturation of nucleocapsids containing full‐length viral DNA. Proc. Natl. Acad. Sci. U.S.A. 79:1423‐1427.
   Wang, Y., Yu, L., and Geller, A.I. 1999. Diverse stabilities of expression in the rat brain from different cellular promoters in a helper virus‐free herpes simplex virus type I vector system. Hum. Gene Ther. 10:1763‐1771.
   Zuffery, R., Nagy, D., Mandel, R.J., Naldini, L., and Trono, D. 1997. Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat. Biotechnol. 15:871‐875.
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