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S. Y. Shukla, Y. K. Singh, D. Shukla; Novel Insights Into Herpes Simplex Virus 2 Entry Into Human Retinal Pigment Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3461.
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Herpes simplex virus-type 2 (HSV-2) is one of the few major viruses that is known to cause Acute Retinal Necrosis (ARN), which can lead to exudative and rhegmatogenous retinal detachment; yet, little is know about the cellular and molecular mechanisms of HSV-2 entry into retinal pigment epithelial (RPE) cells. This study’s goal was to thoroughly investigate these mechanisms, especially the identity of the critical receptors utilized by the virus for entry.
A reporter HSV-2 virus, which expresses β-galactosidase, was used to quantify entry into RPE cells. A plaque assay was used to analyze viral replication. Immunocytochemistry and flow cytometry were used to determine cellular expression of major entry receptors. Localization of these receptors to either the apical or basal surface of RPE cells was determined using immunocytochemistry. The necessity of these receptors, both individually and in combination, for viral entry was established using both siRNA interference and receptor-specific antibodies.
RPE are highly susceptible to HSV-2 entry and develop increasing numbers of plaques over time upon viral infection and replication. Several assays demonstrated the expression of the entry receptors nectin-1, HVEM, and co-receptor PILR-alpha and their localization primarily to the apical surface of RPE cells. siRNA knockdown of receptors and receptor-specific antibodies both led to significantly reduced viral entry and implicated nectin-1 as an important receptor with HVEM and PILR-alpha also contributing to viral entry.
HSV-2 is capable of developing a productive infection in RPE cells by using nectin-1, but also HVEM and PILR-alpha in a novel manner that provides valuable insight into its ability to cause ARN. It also helps to provide a molecular rationale for the human version of the Von Szily reaction.
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