Novel Members of the Human Immunoglobulin Superfamily that Mediate the Entry of Alphaherpesviruses into Cells ( 98025/98018)

The alphaherpesvirus subfamily includes neurotropic viruses such as human HSV-1 and HSV-2 and animal viruses such as porcine pseudorabies virus (PRV) and the bovine herpesvirus BHV-1. Viral entry into cells requires specific interactions of virion glycoproteins with cell surface heparan sulfate and with specific protein receptors.

There are three proteins that can serve as receptors for alphaherpesvirus entry. These three receptors have different cellular distributions and viral specificities. HveA is expressed in lymphocytes and mediates the entry of HSV-1 and HSV-2 but not PRV or BHV-1. HveB is also found in lymphocytes, but its expression is more prominent in epithelial cells, some neuronal cells, and cells of fibroblastic origin. This protein mediates the entry of HSV-2, PRV, and some mutants of HSV-1 that do not enter via HveA; wild-type HSV-1 and BHV-1 are incapable of entry via HveB. HveC is expressed on epithelial cells and neuronal cells and can serve as a receptor for any of the viruses tested. HveB and HveC are likely to be receptors that allow infection at the portal of entry on mucosal surfaces and subsequent spreading to the nervous system.

Investigators at Northwestern University have developed several tools to examine alphaherpes virus entry. Recombinant viruses of wild-type and mutant forms of HSV-1 and -2 are available. These viruses can be used as markers for viral infection as they contain the lacZ gene; thus, infected cells can be identified and infection quantitated by us of beta-galactosidase substrates. Furthermore, Chinese Hamster Ovary cell lines stably expressing HveA, HveB, and HveC have been produced. These cells lines may be used to examine how wild-type and mutant forms of HSV-1 and -2 as well as PRV or BHV-1 bind to and enter cells. Other tools that have been developed include soluble forms of HveA, HveB, and HveC that serve as competitive inhibitors of virus binding. The soluble forms of these receptors may be of use in vaccines or in topical treatments to reduce the spread of lesions at mucosal surfaces or to decrease viral load in herpes patients by inhibiting the ability of virus binding to cellular receptors. Furthermore, the soluble forms of these receptors can be used in gene and peptide therapeutics to treat herpes virus infection.

FIELD OF APPLICATION: The identification of these receptors allows the development and screening of drugs for the prevention and treatment of viral infection in humans and in commercially important animals such as cattle and swine. These reagants also allow for the development of HSV viral vectors for use in gene therapy delivery that target specific cell types.

ADVANTAGES: The identification of the receptors used by herpesviruses provides a new approach for the treatment or prophylaxis of viral infections. The materials identified can lead to the further discovery of additional treatments for herpes virus infection.

STAGE OF DEVELOPMENT: U. S. Patent No. 6,641,818 has issued and Northwestern University is interested in licensing this technology.

Type of Offer: Licensing

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