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Herpes Simplex Virus–Mediated Gene Delivery to the Rodent Visual System

From the Departments of ¹ Medical Microbiology and Immunology and ² Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin.

PURPOSE. To determine the types of cells in the visual system of the mouse and rat that can express a transgene delivered by an attenuated replication competent Herpes simplex virus-1 (HSV-1) vector.

METHODS. C57/BL6 x BALB/C mice and Albino rats were treated with 1 x 10⁷ pfu of the HSV-1 ribonucleotide reductase mutant (hrR3) expressing the Escherichia coli lacZ gene. The hrR3 virus was delivered by topical application to the cornea, intravitreal (IV) injection, intracameral injection (IC), or stereotactic injection into the visual cortex (VC). At specified times postinfection, animals were killed and tissues were removed, fixed, sectioned, and stained with X-gal or hematoxylin and eosin for histochemical and histopathologic examination.

RESULTS. Topical delivery after corneal scarification in both mouse and rat resulted in lacZ expression in 25% of the corneal epithelial cells and 25% of the retinal pigment epithelium (RPE) cells. Topical application without concurrent scarification also resulted in transgene delivery to 20% of the RPE cells of the rat but not the mouse. IV injection resulted in expression primarily in RPE cells, with up to 100% of the cells expressing lacZ in the mouse and rat. Other cells expressing the transgene included ciliary body (CB) and optic nerve cells. Up to 25% of the retinal ganglion cells in the rat expressed lacZ, but only rarely in mice. IC delivery in rats resulted in expression in trabecular meshwork, CB cells, RPE, and iris epithelium. Injection into area 17 of the rat VC resulted in efficient labeling of the VC neurons and neurons in the lateral geniculate nucleus without any evident pathology or inflammation. Neither inflammation nor disease pathology was observed in either the mouse or rat after any route of delivery.

CONCLUSIONS. It was demonstrated that the hrR3 HSV-1 virus can deliver a functioning gene to several cell types in the eye and neurons in the VC and that the virus can move via retrograde transport to nuclei that project to the VC.

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