Protein Eng Des Sel 25:813C820

Protein Eng Des Sel 25:813C820. that the domain was important for VZV fusion. In addition, reduced spread was observed in V knockdown cells infected with the VZV pOka strain relative to that of the control cells. This was demonstrated by reductions in plaque size, replication kinetics, and virion entry in the V subunit knockdown cells. Thus, the V integrin subunit is important for VZV gB/gH-gL fusion and infection. IMPORTANCE Varicella-zoster virus (VZV) 12-O-tetradecanoyl phorbol-13-acetate is a highly infectious pathogen that causes chickenpox and shingles. A common complication of shingles is the excruciating condition called postherpetic neuralgia, which has proven difficult to treat. While a vaccine is now available, it is not recommended for immunocompromised individuals and its efficacy decreases Rabbit Polyclonal to OR with the recipient’s age. These limitations highlight the need for new therapies. This study examines the role of integrins in membrane fusion mediated by VZV glycoproteins gB and gH-gL, a required process for VZV infection. This knowledge will further the understanding of VZV entry and provide insight into the 12-O-tetradecanoyl phorbol-13-acetate development of better therapies. INTRODUCTION Varicella-zoster virus (VZV) is an alphaherpesvirus and a host-specific 12-O-tetradecanoyl phorbol-13-acetate human pathogen that causes the diseases varicella and herpes zoster, commonly known as chickenpox and shingles (1). Prior to the approval of attenuated vaccines by the Food and Drug Administration, varicella was endemic in the United States population and it was estimated that one in three individuals would develop zoster in their lifetime (1, 2). The program for universal varicella vaccination of children in the United States has proven to be successful in preventing disease by reducing varicella incidence by 57% to 90% (3). The zoster vaccine has been effective in reducing the zoster incidence by 51.3% (4). Individuals afflicted with zoster risk developing postherpetic 12-O-tetradecanoyl phorbol-13-acetate neuralgia (PHN), a debilitating, painful condition that can last weeks to months after the acute herpes zoster rash has healed (1). Effective therapies are not currently available to treat PHN, as the cause of pain associated with this condition has not been clarified. While the vaccine can significantly reduce the incidence of herpes zoster and PHN, its effectiveness has been reported to wane over time (5). Critically, the attenuated VZV vaccines are contraindicated for immunocompromised individuals. These limitations highlight the importance of identifying new targets for drug and vaccine development that focus on essential steps in VZV infection. Herpesvirus membrane fusion is an essential first step of virion entry that allows the nucleocapsid to gain access to the cytoplasm of the host cell (6). The formation of the multinucleated cells called syncytia is a consequence of membrane fusion and is associated with VZV-induced pathology in infected skin and neuronal tissue (7, 8). Fusion is induced by a conserved complex of herpesvirus glycoproteins consisting of gB and the heterodimer gH-gL, which are present on the virion and expressed on the surface of infected cells (9). Expression of VZV gB and gH-gL is necessary and sufficient to induce fusion, in contrast to other 12-O-tetradecanoyl phorbol-13-acetate herpesviruses which require additional virally encoded accessory proteins, such as gD for herpes simplex virus (HSV), gp42 for Epstein-Barr virus (EBV) for certain cell types, and gO or UL128/UL130/UL131 for human cytomegalovirus (HCMV) (9,C13). Efforts to identify cellular components that contribute to VZV gB/gH-gL-mediated fusion activity have been hampered by the highly cell-associated nature of VZV in cell culture. This has made it challenging to study the.