Herpes simplex virus type-1 (HSV-1) is highly prevalent among adult human population. The candidate's long-term career goal is to maintain an outstanding research program in studying early events that allow the virus to enter into cells and establish a productive infection for spread. To date, the candidate's research has made a significant contribution to the understanding of HSV-1 entry receptors and uptake mechanisms. Most recently the candidate's laboratory has made new advances in understanding the interactions of HSV-1 with host cells via live cell fluorescence microscopy. The salary support provided by an Independent Scientist Award (K.02) will significantly reduce teaching and administrative responsibilities for the candidate to pursue a new line of research and be more available for the training of graduate students and fellows in the candidate's laboratory, which will enhance their overall productivity. The present proposal extends the research being conducted by the candidate on HSV-1 entry and spread mechanisms. It explores the significance of heparan sulfate (HS) in viral transmission and spread processes. It is based on a novel observation that initial virus-host interactions occur at membrane processes such as filopodia that express HS. This interaction is then exploited by the virus for an efficient and targeted delivery to the cell body for entry and spread to neighboring cells. Although this phenomenon seems to exist for all the herpesviruses examined so far by the candidate and mimic "surfing" phenomenon reported with retroviruses, the exact molecular mechanism for the transport process remain unknown. It is also unclear whether the viruses travel exogenously or intracellularly on the membrane processes. The candidate hypothesizes that the virions travel exogenously until they reach the cell body. Depending on accessibility to entry receptor, the virions either enter into a cell or travel again via membrane processes to reach a neighboring cell body for entry. Experiments will be performed to determine the exogenous nature and the molecular basis of the herpesvirus surfing phenomenon. Significance of the surfing in virus transmission will be addressed using an animal model. The proposed work in this application will provide a new dimension to the current work being done in the candidate's laboratory and it will also open up a new and biomedically significant area for future research.
HSV-1 infections are highly prevalent among humans. About 80% of world's adult population may be seropositive for the virus. The disease manifestations range from more common fever blisters to rare cases of encephalitis. The virus via its envelope proteins interacts with receptors on our cells and this interaction is crucial for the initiation of the infection. Our research may suggest new strategies to stop virus transmission and spread among humans.
|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|
|Antoine, Thessicar E; Yakoub, Abraam; Maus, Erika et al. (2014) Zebrafish 3-O-sulfotransferase-4 generated heparan sulfate mediates HSV-1 entry and spread. PLoS One 9:e87302|
|Yakoub, Abraam M; Rawal, Nistha; Maus, Erika et al. (2014) Comprehensive analysis of herpes simplex virus 1 (HSV-1) entry mediated by zebrafish 3-O-Sulfotransferase isoforms: implications for the development of a zebrafish model of HSV-1 infection. J Virol 88:12915-22|
|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|
|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|
|Hadigal, Satvik; Shukla, Deepak (2013) Exploiting herpes simplex virus entry for novel therapeutics. Viruses 5:1447-65|
|Baldwin, John; Antoine, Thessicar E; Shukla, Deepak et al. (2013) Zebrafish encoded 3-O-sulfotransferase-2 generated heparan sulfate serves as a receptor during HSV-1 entry and spread. Biochem Biophys Res Commun 432:672-6|
|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; Shukla, Deepak (2012) Nonprofessional phagocytosis can facilitate herpesvirus entry into ocular cells. Clin Dev Immunol 2012:651691|
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