Structural and Mechanistic Insights into the Tropism of Epstein-Barr Virus.
Epstein-Barr virus (EBV) is the prototypical γ-herpesvirus and an obligate human pathogen that infects mainly epithelial cells and B cells, which can result in malignancies. EBV infects these target cells by fusing with the viral and cellular lipid bilayer membranes using multiple viral factors and host receptor(s) thus exhibiting a unique complexity in its entry machinery. To enter epithelial cells, EBV requires minimally the conserved core fusion machinery comprised of the glycoproteins gH/gL acting as the receptor-binding complex and gB as the fusogen. EBV can enter B cells using gp42, which binds tightly to gH/gL and interacts with host HLA class II, activating fusion. Previously, we published the individual crystal structures of EBV entry factors, such as gH/gL and gp42, the EBV/host receptor complex, gp42/HLA-DR1, and the fusion protein EBV gB in a postfusion conformation, which allowed us to identify structural determinants and regions critical for receptor-binding and membrane fusion. Recently, we reported different low resolution models of the EBV B cell entry triggering complex (gHgL/gp42/HLA class II) in "open" and "closed" states based on negative-stain single particle electron microscopy, which provide further mechanistic insights. This review summarizes the current knowledge of these key players in EBV entry and how their structures impact receptor-binding and the triggering of gB-mediated fusion.
Department of Microbiology and Immunology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Britta S
BS
Möhl
Department of Microbiology and Immunology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Jia
J
Chen
Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA.
Karthik
K
Sathiyamoorthy
Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA.
Theodore S
TS
Jardetzky
Department of Microbiology and Immunology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Richard
R
Longnecker
D001402:B-Lymphocytes / Q000821:virology; D002460:Cell Line; D004847:Epithelial Cells / Q000821:virology; D005802:Genes, MHC Class II; D004854:Herpesvirus 4, Human / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000378:metabolism*; D056189:Viral Tropism; D053586:Virus Internalization
D000949:Histocompatibility Antigens Class II; D014760:Viral Fusion Proteins
Epstein-Barr virus; entry; fusion; herpesvirus; tropism