Role of Adherens Junction Proteins in Differential Herpes Simplex Virus Type 2 Infectivity in Communication-Competent and -Deficient Cell Lines

Abstract

Background: Gap junctional intercellular communication decreases with HSV-2 infection. To determine the importance of functional gap junctions for infectivity, we compared HSV-2 growth in communication-competent and -deficient cell lines. Methods: HSV-2 infectivity was tested in five cell lines: WB rat liver epithelial cells (communication-competent), WB-aB1 (communication-deficient), WB-a/32-10 (communication-rescued), HeLa (communication-deficient), and Cx43-transfected HeLa (communication-rescued) cells. HSV-2 growth curves and indirect immunofluorescence labeling of viral and cell proteins were performed in wild-type and mutant WB cells. Results: Although wild-type WB cells were highly permissive for HSV-2 infection, virus production was significantly attenuated in communication-deficient and -rescued mutant WB cells. HeLa exhibited no difference in infectivity between communication-competent and -deficient cell lines. Tight and adherens junction proteins, including zonula occludens-1 and nectin-1, were not different in the WB cell lines. However, E-cadherin levels were elevated and β-catenin was found to co-localize with glycoprotein E, a viral glycoprotein associated with cell-to-cell spread, in the mutant WB cells. Conclusions: These results suggest that attenuated viral production in mutant WB cells is due to viral protein co-localization with adherens junction proteins rather than the loss or restoration of functional gap junctions.

Targeting Intercellular Communication in Cancer Gene Therapy

“…Increasing Nectin-1 expression resulted in increased susceptibility to HSV-1 infection and oncolytic activity and hence enhanced tumor regression in vivo [167]. Attenuated HSV-2 viral production in WB rat liver epithelial cells was found to depend on the viral protein co-localization with adherens junction proteins rather than by the status of gap junctions [168]. Taken together, these studies demonstrate the importance of junctional proteins in the infectivity of viruses and suggest that they might impact the efficacy of the viral oncolytic gene therapies.…”

The Causes and Long-Term Consequences of Viral Encephalitis

“…In vitro infection of primary cultures of the mouse brain, endothelial cells with HSV-1 resulted in a downregulation of occludin and claudin-5, along with significant cell apoptosis and Golgi apparatus fragmentation ( Deng et al, 2018 ; He et al, 2020 ). Remarkably, infection of HeLa cells with HSV-2 resulted in no differences in the expression of ZO-1, although this has not been evaluated for HSV-1 ( Miezeiewski et al, 2012 ). Most of these results support the notion that HSV-1 can disrupt the BBB.…”

Novel Gene Therapy Approaches

“…For example, in suicide gene therapy to treat tumors, thymidine kinase gene expression should be restricted to tumor cells [167]. Since hepatocyte growth factor is mitogenic, liver-directed gene transfer is a rational approach to treat liver cirrhosis [168]. To treat inherited gene deficiency diseases such as familial hypercholesterolemia (LDL receptor deficiency in hepatocytes) [169] and Crigler-Najjar syndrome (uridine diphospho-glucuronosyl transferase 1A1 deficiency in hepatocytes) [170], targeted gene delivery is also reasonable due to its efficacy.…”