Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 27;14(11):2372.
doi: 10.3390/v14112372.

How EBV Infects: The Tropism and Underlying Molecular Mechanism for Viral Infection

Guo-Long Bu  1 , Chu Xie  1 , Yin-Feng Kang  1 , Mu-Sheng Zeng  1   2 , Cong Sun  1
Affiliations
Review

How EBV Infects: The Tropism and Underlying Molecular Mechanism for Viral Infection

Guo-Long Bu et al. Viruses. .

Abstract

The Epstein-Barr virus (EBV) is associated with a variety of human malignancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and gastric cancers. EBV infection is crucial for the oncogenesis of its host cells. The prerequisite for the establishment of infection is the virus entry. Interactions of viral membrane glycoproteins and host membrane receptors play important roles in the process of virus entry into host cells. Current studies have shown that the main tropism for EBV are B cells and epithelial cells and that EBV is also found in the tumor cells derived from NK/T cells and leiomyosarcoma. However, the process of EBV infecting B cells and epithelial cells significantly differs, relying on heterogenous glycoprotein-receptor interactions. This review focuses on the tropism and molecular mechanism of EBV infection. We systematically summarize the key molecular events that mediate EBV cell tropism and its entry into target cells and provide a comprehensive overview.

Keywords: Epstein–Barr virus (EBV); disease; entry; infection; tropism.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Model illustrating the infection of EBV in human. EBV is usually transmitted through saliva and first comes across oropharynx and tonsils of the new host, where it primarily infects naïve B cells and possibly memory B cells and epithelial cells as well. EBV establishes latent infection in most naïve B cells, while a small fraction of them might enter productive lytic infection. The latently infected naïve B cells are activated and undergo a phase of rapid expansion as a result of EBV latent gene expression. These activated infected B cells then enter the germinal center (GC), transiting to a more restricted form of viral latency. Finally, the infected B cells differentiate into resting memory B cells, where EBV nearly completely stops its gene expression and maintains its lifelong persistence, but the details of this process are still poorly understood. The EBV-infected resting memory B cells recirculate in the peripheral blood. Under certain stimulations, these resting memory B cells can differentiate into plasma cells, reenter a lytic infection state, and produce infectious virions. These virions lack in gp42 and are more epithelium-tropic. After infecting epithelial cells, the virus replicates lyses the cells, releasing the B-cell-tropic virions with high levels of gp42 into the saliva and starting a new round of transmission. Figdraw (www.figdraw.com) was used to generate this figure.
Figure 2
Figure 2
The process of EBV entry into host cells. (A) Entry of EBV into B cells through endocytosis. Firstly, EBV gp350 attachment with CD21 or CD35, and tethering EBV to B-cell membranes. Then, gH/gL-gp42 binds to receptor HLA class II. This interaction lets gH/gL-gp42 enable interacting with the prefusion form of gB. The interaction leads to a series of structural changes in gB and ultimately fusion of the viral membrane with the cell membrane. Extended rearrangements within gB (intermediate) enables insertion of the fusion loops into the B-cell membrane and the refolding of gB forms post-fusion gB, which mediates the merging of the two membranes. (B) The entry of EBV via direct fusion with epithelial cell membranes. Firstly, gp350/220 interacts with CD21 and/or BMRF2/gH/gL, with integrins tethering EBV to the epithelial cell membrane. After this, gH/gL binds to EphA2/NMHC-IIA or gB interacts with NRP1, producing a membrane fusion signal. The signal is passed to gB and causes a series of changes in its configuration. Extended rearrangements within gB trigger insertion of the fusion loops into the epithelial cell membrane, followed by the refolding of gB to post-fusion form and mediates the merging of the two bilayers. The structures are shown as cartoons: structures of CD21 (2GSX) [97], EBV gp350 (2H6O) [95], the complex of gH/gL (3PHF) [103], the complex of gp42-HLA-DR1 (1KG0) [101], post-fusion gB (3FVC) [98], and EphA2 (2X10) [104] and modified using the PyMOL Molecular Graphics System, Version 2.1.0 Schrödinger, LLC. The structure of integrin alpha5beta1 (3VI4) [105] was used as a representative model of integrins interacting with EBV membrane proteins. The structure files were retrieved from the PDB database. The structure of NMHC-IIA, NRP1, and full-length CD35 are generated by AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Epstein M.A., Achong B.G., Barr Y.M. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;1:702–703. doi: 10.1016/S0140-6736(64)91524-7. - DOI - PubMed
    1. Farrell P.J. Epstein- Barr Virus and Cancer. Annu. Rev. Pathol. Mech. Dis. 2019;14:29–53. doi: 10.1146/annurev-pathmechdis-012418-013023. - DOI - PubMed
    1. WHO. International Agency for Research on Cancer . Epstein-Barr Virus and Kaposi’s Sarcoma Herpesvirus/Human Herpesvirus 8: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 70. IARC; Lyon, France: 1997. 492p - PubMed
    1. De Martel C., Ferlay J., Franceschi S., Vignat J., Bray F., Forman D., Plummer M. Global burden of cancers attributable to infections in 2008: A review and synthetic analysis. Lancet Oncol. 2012;13:607–615. doi: 10.1016/S1470-2045(12)70137-7. - DOI - PubMed
    1. Khan G., Hashim M.J. Global burden of deaths from Epstein-Barr virus attributable malignancies 1990–2010. Infect. Agents Cancer. 2014;9:38. doi: 10.1186/1750-9378-9-38. - DOI - PMC - PubMed

Publication types

Grants and funding

This work was supported by the National Natural Science Foundation of China (82030046 and 81621004), the Guangdong Science and Technology Department (2020B1212030004), and the Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2019BT02Y198).