: The long-term goal of this project is to determine the molecular basis of herpes simplex virus (HSV) invasion of human cells and spread of the virus to neuronal tissues. HSV infection is a major health problem worldwide infecting 60-90% of the world's population, many of which are plagued by initial and recurrent lesions for their entire lives. Adding to that is the morbidity and the risk of blindness from ocular lesions and even lethality of HSV disease in neonates and in increasing number of immunocompromised individuals. The 3-O-sulfated heparan sulfate (3-OS HS) serves as a specific entry receptor for HSV type-1 by offering binding sites for envelope glycoprotein D (gD1). Some recent data suggests that 3-OS HS can mediate all forms of primary infection, from HSV-1 entry into cells to cell-to-cell spread of the virus by mediating cell fusion. The cell-to-cell fusion as well as the fusion of the viral envelope with host cell membrane appear to require gD/3-OS HS complex in concert with three additional viral glycoproteins, gB, gH and gL. It is not clear how the receptor binding triggers the sequence of events that result in fusion. Extensive studies involving gD1 (wild-type and mutant forms), gD2, and 3-OS HS variants will be performed to develop a better understanding of the structural and biochemical requirements for a productive interaction between gD and 3-OS HS. Multiple assays that include in vitro and in vivo binding of 3-OS HS with gD, cell fusion, and viral entry will be used. Further, to determine the significance of 3-OS HS in HSV-1 entry, studies will be performed in some natural target cells to examine expression and the potential contribution of 3-OS HS in tissue tropism. These studies will be aided by the use of primary cell cultures, protein expression assays, novel peptides generated by phage display screening, and siRNA (small-interfering RNA) technology. The reagents generated would also be useful for evaluating other biological functions of 3-OS HS as well. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI057860-01A2
Application #
6922486
Study Section
Virology - B Study Section (VIRB)
Program Officer
Beisel, Christopher E
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
1
Fiscal Year
2005
Total Cost
$305,826
Indirect Cost
Name
University of Illinois at Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Antoine, Thessicar E; Shukla, Deepak (2014) Inhibition of myosin light chain kinase can be targeted for the development of new therapies against herpes simplex virus type-1 infection. Antivir Ther 19:15-29
Baldwin, John; Shukla, Deepak; Tiwari, Vaibhav (2013) Members of 3-O-Sulfotransferases (3-OST) Family: A Valuable Tool from Zebrafish to Humans for Understanding Herpes Simplex Virus Entry. Open Virol J 7:5-11
Baldwin, John; Park, Paul J; Zanotti, Brian et al. (2013) Susceptibility of human iris stromal cells to herpes simplex virus 1 entry. J Virol 87:4091-6
Choudhary, Samiksha; Burnham, Lorrie; Thompson, Jeffrey M et al. (2013) Role of Filopodia in HSV-1 Entry into Zebrafish 3-O-Sulfotransferase-3-Expressing Cells. Open Virol J 7:41-8
Park, Paul J; Antoine, Thessicar E; Farooq, Asim V et al. (2013) An investigative peptide-acyclovir combination to control herpes simplex virus type 1 ocular infection. Invest Ophthalmol Vis Sci 54:6373-81
Park, Paul J; Shukla, Deepak (2013) Role of heparan sulfate in ocular diseases. Exp Eye Res 110:1-9
Antoine, Thessicar E; Park, Paul J; Shukla, Deepak (2013) Glycoprotein targeted therapeutics: a new era of anti-herpes simplex virus-1 therapeutics. Rev Med Virol 23:194-208
Tiwari, Vaibhav; Maus, Erika; Sigar, Ira M et al. (2012) Role of heparan sulfate in sexually transmitted infections. Glycobiology 22:1402-12
Antoine, Thessicar E; Mishra, Yogendra K; Trigilio, James et al. (2012) Prophylactic, therapeutic and neutralizing effects of zinc oxide tetrapod structures against herpes simplex virus type-2 infection. Antiviral Res 96:363-75
Salameh, Sarah; Sheth, Urmi; Shukla, Deepak (2012) Early events in herpes simplex virus lifecycle with implications for an infection of lifetime. Open Virol J 6:1-6

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