Efficient infection of mature skeletal muscle with herpes simplex virus vectors by using dextran sulfate as a co-receptor.
The use of herpes simplex virus (HSV) vectors for gene delivery to skeletal muscle is hampered by a maturation-dependent loss of muscle fiber infectivity. Previous studies of HSV type 1 (HSV-1) infection in the rodent show that the loss of infectivity may be due, at least in part, to the development of the basal lamina throughout the course of maturation, which may block the initial events in HSV infection. To initiate infection, HSV normally attaches to cell surface heparan sulfate, which stabilizes the virus such that it can interact with secondary protein receptors required for entry into host cells. In this study, we demonstrate that heparan sulfate biosynthesis is downregulated during skeletal muscle maturation. When myofibers were treated with a variety of enzymes, including collagenase type IV or chondroitin ABC lyase, HSV infection was restored, which suggests that virus secondary receptors were present but not readily accessible to the virus in the intact myofiber. Surprisingly, we also found that HSV-1 infectivity could be restored in vitro and in vivo by exposing myofibers to low concentrations of the glycosaminoglycan analog dextran sulfate, which appears to act as a surrogate receptor to stabilize the virus at the myofiber surface such that HSV can engage additional receptors. This demonstration that the basal lamina is not an absolute block to HSV-1 infection is remarkable because it allows for the nondestructive targeting of HSV-1 to mature myofibers and greatly expands the usefulness of HSV as a gene therapy vector for the treatment of inherited and acquired diseases.
Yeung
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Department of Microbiology and Immunology, University of British Columbia, 300-6174 University Boulevard, Vancouver, BC Canada, V6T 1Z3.
Bockhold
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Tufaro
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D000375:Aging; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016264:Dextran Sulfate; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000821:virology*; D011991:Receptors, Virus / Q000235:genetics*; D018139:Simplexvirus / Q000235:genetics*; D016662:Virus Integration
D011991:Receptors, Virus; D016264:Dextran Sulfate