Replication-Competent Controlled Herpes Simplex Virus

被引:10
|
作者
Bloom, David C. [1 ]
Feller, Joyce [1 ]
McAnany, Peterjon [1 ]
Vilaboa, Nuria [2 ,3 ]
Voellmy, Richard [4 ,5 ]
机构
[1] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL USA
[2] Hosp Univ La Paz, IdiPAZ, Madrid, Spain
[3] CIBER Bioingn Biomat & Nanomed, Barcelona, Spain
[4] HSF Pharmaceut SA, La Tour De Peilz, Switzerland
[5] Univ Florida, Coll Vet Sci, Dept Physiol Sci, Gainesville, FL USA
关键词
SHOCK TRANSCRIPTION FACTOR; HEAT-SHOCK; SPATIOTEMPORAL CONTROL; PREEXISTING IMMUNITY; ECDYSONE RECEPTOR; GENE SWITCHES; EXPRESSION; VECTOR; RECOMBINANT; PROTEINS;
D O I
10.1128/JVI.01667-15
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
We present the development and characterization of a replication-competent controlled herpes simplex virus 1 (HSV-1). Replication-essential ICP4 and ICP8 genes of HSV-1 wild-type strain 17syn+ were brought under the control of a dually responsive gene switch. The gene switch comprises (i) a transactivator that is activated by a narrow class of antiprogestins, including mifepristone and ulipristal, and whose expression is mediated by a promoter cassette that comprises an HSP70B promoter and a transactivator-responsive promoter and (ii) transactivator-responsive promoters that drive the ICP4 and ICP8 genes. Single-step growth experiments in different cell lines demonstrated that replication of the recombinant virus, HSV-GS3, is strictly dependent on an activating treatment consisting of administration of a supraphysiological heat dose in the presence of an antiprogestin. The replication-competent controlled virus replicates with an efficiency approaching that of the wild-type virus from which it was derived. Essentially no replication occurs in the absence of activating treatment or if HSV-GS3-infected cells are exposed only to heat or antiprogestin. These findings were corroborated by measurements of amounts of viral DNA and transcripts of the regulated ICP4 gene and the glycoprotein C (gC) late gene, which was not regulated. Similar findings were made in experiments with a mouse footpad infection model. IMPORTANCE The alphaherpesviruses have long been considered vectors for recombinant vaccines and oncolytic therapies. The traditional approach uses vector backbones containing attenuating mutations that restrict replication to ensure safety. The shortcoming of this approach is that the attenuating mutations tend to limit both the immune presentation and oncolytic properties of these vectors. HSV-GS3 represents a novel type of vector that, when activated, replicates with the efficiency of a nonattenuated virus and whose safety is derived from deliberate, stringent regulation of multiple replication-essential genes. By directing activating heat to the region of virus administration, replication is strictly confined to infected cells within this region. The requirement for antiprogestin provides an additional level of safety, ensuring that virus replication cannot be triggered inadvertently. Replication-competent controlled vectors such as HSV-GS3 may have the potential to be superior to conventional attenuated HSV vaccine and oncolytic vectors without sacrificing safety.
引用
收藏
页码:10668 / 10679
页数:12
相关论文
共 50 条
  • [41] Oncolytic viral therapy for human ovarian cancer using a novel replication-competent herpes simplex virus type I mutant in a mouse model
    Nawa, A
    Nozawa, N
    Goshima, F
    Nagasaka, T
    Kikkawa, F
    Niwa, Y
    Nakanishi, T
    Kuzuya, K
    Nishiyama, Y
    GYNECOLOGIC ONCOLOGY, 2003, 91 (01) : 81 - 88
  • [42] Attenuated, replication-competent herpes simplex virus type 1 mutant G207: Safety evaluation of intracerebral injection in nonhuman primates
    Hunter, WD
    Martuza, RL
    Feigenbaum, F
    Todo, T
    Mineta, T
    Yazaki, T
    Toda, M
    Newsome, JT
    Platenberg, RC
    Manz, HJ
    Rabkin, SD
    JOURNAL OF VIROLOGY, 1999, 73 (08) : 6319 - 6326
  • [43] ISOLATION OF REPLICATION-COMPETENT MOLECULAR CLONES OF VISNA VIRUS
    STASKUS, KA
    RETZEL, EF
    LEWIS, ED
    SILSBY, JL
    STCYR, S
    RANK, JM
    WIETGREFE, SW
    HAASE, AT
    COOK, R
    FAST, D
    GEISER, PT
    HARTY, JT
    KONG, SH
    LAHTI, CJ
    NEUFELD, TP
    PORTER, TE
    SHOOP, E
    ZACHOW, KR
    VIROLOGY, 1991, 181 (01) : 228 - 240
  • [44] Herpes simplex virus type 1 DNA amplified as bacterial artificial chromosome in Escherichia coli:: Rescue of replication-competent virus progeny and packaging of amplicon vectors
    Saeki, Y
    Ichikawa, T
    Saeki, A
    Chiocca, EA
    Tobler, K
    Ackermann, M
    Breakefield, XO
    Fraefel, C
    HUMAN GENE THERAPY, 1998, 9 (18) : 2787 - 2794
  • [45] Replication-competent herpes virus NV1020 as direct treatment of pleural cancer in a rat model
    Ebright, MI
    Zager, JS
    Malhotra, S
    Delman, KA
    Weigel, TL
    Rusch, VW
    Fong, Y
    JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 2002, 124 (01): : 123 - 129
  • [46] Replication-competent hybrids between murine leukemia virus and foamy virus
    Shikova-Lekova, E
    Lindemann, D
    Pietschmann, T
    Juretzek, T
    Rudolph, W
    Herchenröder, O
    Gelderblom, HR
    Rethwilm, A
    JOURNAL OF VIROLOGY, 2003, 77 (13) : 7677 - 7681
  • [47] Phase I Trial of Intratumoral (IT) Administration of HF10, a Replication-Competent Herpes Simplex Virus Type 1, in Patients with Refractory Superficial Cancer
    Ferris, Robert L.
    Nemunaitis, John
    Argiris, Athanassios
    Gross, Neil
    Smith, Russell
    Senzer, Neil
    Bedell, Cynthia
    Ungerleider, Richard S.
    Tanaka, Maki
    Nishiyama, Yukihiro
    MOLECULAR THERAPY, 2012, 20 : S83 - S83
  • [48] In situ cancer vaccination: An IL-12 defective vector replication-competent herpes simplex virus combination induces local and systemic antitumor activity
    Toda, M
    Martuza, RL
    Kojima, H
    Rabkin, SD
    JOURNAL OF IMMUNOLOGY, 1998, 160 (09): : 4457 - 4464
  • [49] Herpes simplex virus DNA replication
    Boehmer, PE
    Lehman, IR
    ANNUAL REVIEW OF BIOCHEMISTRY, 1997, 66 : 347 - 384
  • [50] Replication of herpes simplex virus DNA
    Lehman, IR
    Boehmer, PE
    JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (40) : 28059 - 28062