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The Tetraspanin Protein CD9 Modulates Infection with Human Herpesvirus 6A and 6B in a CD46-Dependent Manner

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Tetraspanins are four-span transmembrane proteins that organize the membrane by forming tetraspanin-enriched microdomains. These have been shown to be important for virus entry. The human herpesvirus-6A (HHV-6A) receptor CD46 is known to form complexes with the tetraspanin CD9 and b1-integrins; however, the significance of this for HHV-6A infection remains unexplored. Using a genetic approach, we demonstrate that knockout of CD46 abolishes binding to and infection of SupT1 cells by both HHV-6A and HHV-6B, establishing CD46 as a necessary receptor for productive infection of these cells. Knockout of CD9 in SupT1 cells had no effect on binding of either virus to the cell surface, but it reduced expression of immediate early transcripts to between 25 and 60%, compared with wild-type cells. Although HHV-6B required CD46 for infection of SupT1, infection of Molt3 cells was independent of CD46 expression. Conversely, the absence of CD9 expression promoted infection of Molt3 cells with HHV-6B, indicating a negative role of CD9 for CD46-independent infection. Taken together, these data demonstrate that CD9 modulates infection with HHV-6A/B by promoting CD46-dependent infection and impairing CD46-independent infection. This also suggests that HHV-6A is strictly dependent on CD46 for entry, although other proteins, like CD9, may enhance the infection, whereas HHV-6B is more promiscuous and may use CD134, as demonstrated by others, CD46 in SupT1 cells, and a novel unidentified receptor in Molt3 cells.

IMPORTANCE The mechanisms of entry of HHV-6A and HHV-6B into host cells are of significance in order to develop novel drugs that may inhibit infection. To elucidate the contributions of the membrane proteins CD9 and CD46, we employed a genetic approach that eliminated these molecules from the host cell. This demonstrated that CD46 is critical for infection by HHV-6A, whereas infection by HHV-6B appeared to be more promiscuous. The infection of a T-cell line in the absence of CD46 and CD134 strongly suggests that an additional receptor for HHV-6B entry exists. Moreover, elimination of CD9 and subsequent reconstitution experiments demonstrated that CD9 promoted infection with HHV-6A and HHV-6B mediated by CD46 but inhibited infection with HHV-6B that occurred independent of CD46. Together, this demonstrated a CD46-dependent role of CD9 during infection with HHV-6A and HHV-6B and emphasized that HHV-6B may employ different entry mechanisms in various cells.

Original languageEnglish
Article numbere02259-20
JournalJournal of Virology
Number of pages15
Publication statusPublished - Mar 2021

    Research areas

  • CD46, CD9, HHV-6A, HHV-6B, Human herpesvirus 6A, Human herpesvirus 6B, Tetraspanin

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