gp96 Is Critical for both Human Herpesvirus 6A (HHV-6A) and HHV-6B Infections

Abstract

Human herpesviruses 6A and 6B (HHV-6A and HHV-6B, respectively) are two virus species in the beta herpesvirus subfamily that exhibit T cell tropism. CD46 and CD134 are the cellular receptors for HHV-6A and HHV-6B, respectively. Interestingly, the efficiency of HHV-6A/6B entry is different among different types of target cells despite similar receptor expression levels on these cells. Here, we found that the cellular factor gp96 is expressed on the cell surface and interacts with the viral glycoprotein Q1 (gQ1) during virus entry. gp96 cell surface expression levels are associated with the efficiency of HHV-6A and HHV-6B entry into target cells. Both loss-of-function and gain-of-function experiments indicated that gp96 plays an important role in HHV-6 infection. Our findings provide new insight into the HHV-6 entry process and might suggest novel therapeutic targets for HHV-6 infection. IMPORTANCE Although new clinical importance has been revealed for human herpesviruses 6A and 6B, much is still unknown about the lifecycles of these viruses in target cells. We identified a novel cellular factor, gp96, that is critical for both HHV-6A and -6B entry into host cells. As gp96 can function as an adjuvant in vaccine development for both infectious agents and cancers, it can be a potential therapeutic target for infection by these two viruses.