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

Human herpesviruses 6A and 6B (HHV-6A and HHV-6B, respectively) are two virus species in the betaherpesvirus 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 (also known as glucose-regulated protein 94 [GRP94]) is expressed on the cell surface and interacts with 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 (HHV-6A) and 6B, much is still unknown about the life cycles 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.