CD81 is an Ebola virus inhibiting factor that is antagonized by GP and VP40

Abstract Viruses manipulate the host cell membrane of infected cells for evasion of antiviral immunity, prevention of superinfection and optimization of viral replication and spread. The Ebola virus glycoprotein (EBOV GP) mediates virus entry, but is also known as important factor for subversion of the host’s antiviral immune response. We characterized the dysregulation of cell surface-residing proteins by EBOV GP and found that among several membrane proteins GP interferes with the tetraspanins CD81, CD63 and CD9. This was a conserved function of several filoviral GPs and not observable for viral glycoproteins of other virus families. While CD63 and CD9 were largely dispensable for EBOV replication, CD81 suppressed virus-like particle entry and replication at multiple steps. This phenotype might be explainable by sustained suppression of NFκB by CD81, that is otherwise activated by VP40 and EBOV trVLP replication. We further demonstrate that not only GP but also VP40 interferes with CD81 functionality and that antibody-mediated clustering of CD81 suppresses EBOV infection. Altogether, the tetraspanin CD81 emerges as druggable NFκB and EBOV-inhibiting factor, supporting an important role of NFκB in EBOV replication and potentially virus-induced immunopathogenesis. Highlights EBOV GP and VP40 interfere with CD81 cell surface expression CD81 suppresses NFκB signaling which is activated by VP40 CD81 restricts EBOV VLP uptake and replication Targeting CD81 by a crosslinking antibody inhibits EBOV infection Competing Interest Statement The authors have declared no competing interest.