Work

155. Soluble HVEM Mediates Herpes Simplex Virus 1 (HSV-1) Infection of gD Receptor-Negative Cells

Year: 2006

Type: article

Abstract: Herpes simplex virus infects a broad range of mammalian cells, including epithelial cells, lymphocytes, and postmitotic neurons. HSV-1 entry into cells is initiated by the binding of viral envelope glycoprotein D (gD) to one of three known HSV entry receptors, nectin-1/HveC, HVEM/HveA, and 3-O-sulfotransferase-modified heparan sulfate. Interaction of gD with these entry receptors is believed to cause a conformational change in gD, enabling it to interact with other envelope components which ultimately results in fusion of the viral envelope with the cell membrane. The other players in these events and their specific roles remain largely unknown. The broad host range of HSV-1 is an obstacle in the development of this virus into a gene vector for therapeutic applications. Replication-selective mutants and transcriptional targeting have been used to avert this problem. As an alternative, we are studying the utility of soluble gD receptors which are capable of inhibiting the infection of susceptible cells. We previously reported that the soluble V domain of nectin-1/HveC in addition has the ability to mediate efficient infection of HSV-resistant, receptor-deficient CHO-K1 cells. We now show that this property is not unique to nectin-1. We constructed a set of truncated, soluble forms of HVEM/HveA and examined their effects on HSV-1 infection of resistant CHO-K1 cells and susceptible derivatives. In cultures of CHO-K1 cells, sHveA102 caused infection of greater than 90% of the cells at an MOI of 3 using a lacZ-expressing virus, KOS/tk12. In contrast, sHveA162 did not mediate virus entry into these cells. Both sHveA102 and sHveA162 blocked KOS/tk12 infection of CHO-K1 cells stably expressing HVEM/HveA in a dose-dependent manner, indicating that both were capable of binding to viral gD. We suggest that sHveA162, unlike sHveA102, prevents the folding of gD into an active conformation that can trigger the fusion process. Together, these results show that sHveA162 may be utilized to restrict the natural host range of HSV-1 and that sHveA102 combines the properties of limited size and unimpaired activation of gD that can make it a desirable component of HSV targeting adapters.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2006.08.178