Reduction in severity of a herpes simplex virus type 1 murine infection by treatment with a ribozyme targeting the UL20 gene RNA.
Hammerhead ribozymes were designed to target mRNA of several essential herpes simplex virus type 1 (HSV-1) genes. A ribozyme specific for the late gene U(L)20 was packaged in an adenovirus vector (Ad-U(L)20 Rz) and evaluated for its capacity to inhibit the viral replication of several HSV-1 strains, including that of the wild-type HSV-1 (17syn+ and KOS) and several acycloguanosine-resistant strains (PAAr5, tkLTRZ1, and ACGr4) in tissue culture. The Ad-U(L)20 Rz was also tested for its ability to block an HSV-1 infection, using the mouse footpad model. Mouse footpads were treated with either the Ad-U(L)20 Rz or an adenoviral vector expressing green fluorescent protein (Ad-GFP) and then infected immediately thereafter with 10(4) PFU of HSV-1 strain 17syn+. Ad-U(L)20 ribozyme treatment consistently led to a 90% rate of protection for mice from lethal HSV-1 infection, while the survival rate in the control groups was less than 45%. Consistent with this protective effect, treatment with the Ad-U(L)20 Rz reduced the viral DNA load in the feet, the dorsal root ganglia, and the spinal cord relative to that of the Ad-GFP-treated animals. This study suggests that ribozymes targeting essential genes of the late kinetic class may represent a new therapeutic strategy for inhibiting HSV infection.
Department of Molecular Genetics and Microbiology, Box 100266, University of Florida College of Medicine, Gainesville, FL 32610-0266, USA.
Jia
J
Liu
Alfred S
AS
Lewin
Sonal S
SS
Tuli
Steven C
SC
Ghivizzani
Gregory S
GS
Schultz
David C
DC
Bloom
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000627:therapeutic use*; D004279:DNA, Viral / Q000235:genetics; D005528:Foot / Q000821:virology; D005727:Ganglia, Spinal / Q000821:virology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics; D007700:Kinetics; D051379:Mice; D016337:RNA, Catalytic / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D013116:Spinal Cord / Q000821:virology; D016019:Survival Analysis; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
D000998:Antiviral Agents; D004279:DNA, Viral; D016337:RNA, Catalytic; C121742:UL20 protein, Herpes simplex virus type 1; D014764:Viral Proteins; C427204:hammerhead ribozyme