Gammaherpesvirus entry and fusion: A tale how two human pathogenic viruses enter their host cells

Abstract

The prototypical human γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi Sarcomaassociated herpesvirus (KSHV) are involved in the development of malignancies. Like all herpesviruses, they share the establishment of latency, the typical architecture, and the conserved fusion machinery to initiate infection. The fusion machinery reflects virus-specific adaptations due to the requirements of the respective herpesvirus. For example, EBV evolved a tropism switch involving either the B-or epithelial cell-tropism complexes to activate fusion driven by gB. Most of the EBV entry proteins and their cellular receptors have been crystallized providing molecular details of the initial steps of infection. For KSHV, a variety of entry and binding receptors has also been reported but the mechanism how receptor binding activates gB-driven fusion is not as well understood as that for EBV. However, the downstream signaling pathways that promote the early steps of KSHV entry are well described. This review summarizes the current knowledge of the key players involved in EBV and KSHV entry and the cell-type specific mechanisms that allow infection of a wide variety of cell types.

Towards Understanding KSHV Fusion and Entry

“…In the absence of atomic resolution structures for gB, models were generated in silico using the SWISS-MODEL program [127] and provide some fascinating potential insight into functions of the molecule until a KSHV structure can verify them. The post-fusion structure of EBV gB was used to model KSHV gB [23,128,129]. The model predicts that, like other herpesvirus gB homologs, KSHV gB is comprised of five distinct functional domains and is homologous to type III fusion glycoproteins.…”

“…A gHgL structural model was also created based on the EBV structures and the model predicts several virus-specific adaptations [23,60,136,137]. gH is predicted to have four domains and binds noncovalently to the smaller gL which is comprised of a single domain.…”

“…A host-derived lipid bilayer termed the viral envelope is the last layer that surrounds the whole particle [22]. Viral envelope glycoproteins transverse the viral envelope and are responsible for the initial virus–host interactions [23,24]. Viral envelope glycoproteins K8.1A, glycoprotein-B (gB), and the heterodimer of glycoprotein- H and glycoprotein-L (gHgL) are widely regarded as the most important for virus entry and are the best understood of the KSHV glycoproteins.…”

Molecular basis of EphA2 recognition by gHgL from gammaherpesviruses

“…Epstein-Barr virus (EBV, Lymphocryptovirus) and Kaposi sarcoma-associated herpesvirus (KSHV, Rhadinovirus) are the only two human-infecting γ-herpesviruses. EBV and KSHV have many commonalities, such as an association with malignancies, broad cell tropism, and a similar entry process into host cells [2][3][4] . EBV primarily infects B cells and epithelial cells 5 , whereas KSHV predominantly infects B cells and endothelial cells.…”

“…The process by which herpesviruses enter cells is divided into three steps: attachment, receptor binding, and fusion. These steps are mediated by different viral glycoproteins 2,6 . Cell tropism is mainly determined by the interaction between a specific host receptor and the gHgL complex, with or without other glycoproteins 7 .…”