Epstein-Barr Virus (EBV)

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Epstein Barr Virus (EBV)

Classification

Epstein-Barr Virus (EBV) was discovered in 1964 from a line of Burkitt Lymphoma cells. EBV is part of the herpes family, the gammaherpesviruses subfamily and the Lymphocryptovirus genus 1, but EBV is known as human herpesvirus 4 or HHV-4.


Introduction

The Epstein Barr virus is associated with infectious mononucleosis (IM), which affects over 3 million people in the US each year (2). There are two types of EBV, type 1 and type 2. Studies have shown that signs of an EBV infection can be found in 95% of the world’s population, most of which is in the latent form (2). In addition to its role in IM, EBV is thought to contribute to the development of B-cell lymphoma, nasopharyngeal carcinoma, gastric carcinoma (3), autoimmune diseases (4), and Post-transplant lymphoproliferative disease (PTLD)(5). Post-transplant lymphoproliferative disease (PTLD) has been shown to be linked with the reactivation of latent EBV in transplant patients and remains a point of interest in the ongoing research of EBV (5). Additionally, other studies link EBV to autoimmune diseases such as lupus, rheumatoid arthritis (RA), and multiple sclerosis (MS) and current studies are being done to test how effective EBV antigens are in treating these diseases (4). There is a large variety of research being conducted with the EBV virus because of the different ways that EBV can manifest within the human host (2) and the hope that a vaccine can be created (6).


Genome structure

EBV is a double stranded DNA virus with approximately 184 kb pairs, coding for almost 100 proteins (2). The number of proteins in EBV are what allow for the regulation and replication of the viral genes and assist in following how the immune system of the host responds to the infection (7). EBV’s genome is divided into unique long and short repeat regions, which allows for EBV strains to be distinguished from one another (5). EBV terminal DNA repeats bring about circularization in infected cells, and just one terminal segment can determine infection at an early phase (8). In humans, EBV can be cancer causing so it is a virus commonly called oncogenic because EBV keeps the cancer cell alive even though it is infecting the cell. Currently, there are four strains of Epstein-Barr Virus published and these strains are linked to a number of serious diseases along with cancer such as Lymphoma or nasopharyngeal carcinoma (5).


Cell structure & Metabolic processes

Epstein-Barr Virus is made up of a toroid shaped protein core that is surrounded by the linear double-stranded DNA. Around that is an icosahedral nucleocapsid with 162 capsomeres within it (9). Then, EBV has a protein segment that surrounds the capsid and an outer viral envelope. The structure of EBV is based on the fact it is so similar to the other herpesviruses with the capsid and a membrane with surface glycoproteins (9).


EBV can cause a number of malignancies and it has been proven through high levels of glycolysis in certain cell lines (10). Glycolysis occurs during the latency period of EBV infection and is a source of ATP for the cell. The Warburg effect is a process observed in most cancer cells and consist of the quick generation of ATP through the glycolytic pathway as a way to continue rapid growth (3). One study documented an increase in glucose use through the glycolytic pathway of EBV infected cells, where control cells did not show an increase. The study suggested that EBV infected cells could become carcinogenic within the host, leading to the Warburg effect being observed within the cell (3). Rise in glucose levels also feed the other metabolic pathways EBV needs to continue with viral infection, such as fatty acid synthesis during its lytic replication, which allows for further proliferation (10).


Ecology

Since EBV is not alive it requires a host to live. Other EBV like viruses can be found in many animals, but humans are the only host for EBV and the infection can remain latent in humans for many years (1). EBV maintains it latent state within the B lymphocytes of the human host. While in the host EBV adapts the B lymphocytes to become “proliferation machines” (12). Essentially, the B lymphocytes are turned into lymphoblastoid cell lines (LCL’s), which have the ability to proliferate rapidly and without end (11). In a healthy host, cytotoxic T lymphocytes control the proliferation, but immunocompromised patients (typically transplant or AIDS patients) can have unchecked proliferation by the LCL’s, leading to AIDS associated lymphoma or PTLD (11).


File:EBV infection cycle in healthy humans.png
Figure 1. Public Image from Wikipedia Commons: The figure demonstrates how EBV enters into the cell and convert B lymphocytes into LCL’s. The rest of the life cycle, including latency, reactivation, and lysis, is then shown.


Pathology

EBV is spread between hosts primarily by mucosal contact with uninfected individuals. Nearly all individuals will become infected with EBV in their lifetime, but there is a temporal difference in infection between developed and undeveloped countries (12). In undeveloped countries asymptomatic infection is common among infancy or early childhood. In contrast, EBV infection in developed nations most commonly occurs in adolescence, which is not asymptomatic (12). Termed “the kissing disease”, adolescents become infected when saliva is exchanged in their contact with others. This causes infectious mononucleosis (IM) (12). IM is characterized by high fever, enlarged lymph nodes, severe sore throat, body aches, and malaise. It is diagnosed by a blood test for the viral proteins: nuclear envelope (Epstein-Barr Nuclear Antigen or EBNA), and the viral capsid antigen (Epstein-Barr Viral Capsid Antigen) (12). The virus enters the immune system to target B lymphocytes through the tonsils.


When B lymphocytes are infected with EBV, it causes them to proliferate uncontrollably, similarly seen in cancer cells (12). However, the uncontrollable proliferation does not impact the B lymphocyte’s ability to produce antibodies against the virus, and it is these viral antibodies that diagnostic tests look for. The antibodies cause recruitment of CD8+ cytotoxic T cells, which ultimately control primary infection by attacking infected B lymphocytes (12). It is for this reason that most IM cases caused by EBV are self-limiting (12).


However, the virus inserts the genome into the DNA of B lymphocytes where it may remain latent for years. Those who become immunocompromised from illness (such as HIV patients) or patients taking immunosuppressive treatments for cancer or other illnesses of the immune system may experience reinfection (12). In the development of HIV infection to full AIDS, HIV suppresses the T cells, leading to a lack of control over EBV reactivation.(12)


EBV is implicated in many cancers, however its role in transformation to neoplastic cells (except in the case of Burkitt’s Lymphoma) has yet to be confirmed by consensus in the scientific community.

  • Burkitt’s Lymphoma: EBV is required for this cancer of the B lymphocytes, along with malaria infection and constitutive expression of the c-myc oncogene.(13)
  • Hodgkin’s Lymphoma: EBV is present in over 50% of cases of this lymphoma in the US, and in undeveloped nations it may be present in up to 100% of cases due to asymptomatic childhood infection. (13)
  • Nasopharyngeal Carcinoma (NPC): NPC is may develop as differentiated (lymphatic tissue dispersed among nasopharyngeal epithelial tissue) or undifferentiated (lymphatic tissue is separate from the nasopharyngeal epithelial tissue. Undifferentiated NPC 100% of the time is found to have been infected with EBV. (13)


Current Research

A main focus of current research being done is to determine what diseases are linked to the Epstein Barr virus. As mentioned, post-transplantation lymphoproliferative disease (PTLD), some autoimmune diseases, and lymphoid cancers are linked to EBV and research is being conducted to determine the connection between the virus and diseases. PTLD is a complication that occurs after organ transplants and hematopoietic stem cell transplants (14). Research has recently shown that one of the triggers of PTLD onset occurs after transplantation, when EBV is reactivated (14). The main research being done on PTLD involves treatment of the disease. PTLD can be treated through cellular immunotherapy, but the issue lies in difficulty creating EBV-specific T-cells, which are the cells that can prevent EBV, in a short amount of time (14). After conducting various research methods, it was discovered that ex vivo transfer of EBV nuclear antigen 1-specific T cells can solve the issue of creating EBV specific T cells in a short amount of time, and can help to prevent PTLD (14).


An autoimmune disease with no known cause and is very different from PTLD, Rheumatoid arthritis (RA), was investigated to determine if EBV contributed to the onset of the disease (15). Research revealed that patients with RA have a high concentration of anti-EBV antibodies, an abnormally high amount of B cells infected with EBV, and a large concentration of EBV in the blood (15). Other research delves into the connection between EBV and gastric carcinoma. Specifically, research has found Epstein Barr virus associated Gastric Carcinoma (EBVaGC), which is a type of gastric carcinoma (16). Research has shown that EBV is not a direct cause of EBVaGC, but rather a series of processes affect EBV function, which in turn affect gene expression (16). In EBVaGC, the EBV genome is hypermethylated due to increased activation of DNA methyltransferase, which leads to latent genes becoming less expressed, and thus causes the virus to not signal a response from the immune system (16). So, EBV does not directly cause this response, as research has shown it is a multitude of effects that cause the lack of immune response, which is associated with the onset of EBVaGC (16). There is still much research being done on the effects of EBV on various diseases, including Burkitt’s lymphoma and non-Hodgkin’s lymphoma, and how the relationship between the virus and the diseases can help with prevention of the diseases (15).


There is also progress in creating an EBV vaccine. One of the most prevalent studies of EBV vaccines in humans involves infectious mononucleosis (IM), a disease associated with EBV (17). In the study, uninfected young adults were vaccinated with recombinant gp350 (17). Gp350 was purified from Chinese hamster ovary cells and expressed the glycoprotein (17). Although the vaccine was found to not protect against EBV, it did greatly reduce IM incidence (17). Currently, this g350 vaccine is being developed, despite the fact that it does not protect against EBV (17).



Citations
  1. “Epstein-Barr Virus.” Biological Agents, vol. 100B, International Agency for Research on Cancer, 2012.
  2. Junker, Anne et al. “Epstein-Barr Virus.” Pediatrics in Review, 2005, pp. 79-84.
  3. Xiao, L et al. “Targeting Epstein–Barr Virus Oncoprotein LMP1-Mediated Glycolysis Sensitizes Nasopharyngeal Carcinoma to Radiation Therapy.” Oncogene. vol. 33 no.37, 2014, pp. 4568–4578.
  4. Giovanni Capone, et al. “EBV-Associated Cancer and Autoimmunity: Searching for Therapies.” Vaccines, vol. 3, no. 1, 2015, pp. 74–89.
  5. Luzuriaga, K., & Sullivan, J. L. “Epstein-Barr virus.” Clinical Virology, Third Edition. 2006, pp. 521-536.
  6. Kanekiyo, et al. “Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site.” Cell, vol. 162, no. 5, 2015, pp. 1090–1100.
  7. Kieff, E.D. et al. “Epstein Barr Virus.” Fields Virology. 2007, p. 3091.
  8. Icheva, et al. “Adoptive Transfer of Epstein-Barr Virus (EBV) Nuclear Antigen 1-Specific t Cells as Treatment for EBV Reactivation and Lymphoproliferative Disorders after Allogeneic Stem-Cell Transplantation.” Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 31, no. 1, 2013, pp. 39–48.
  9. Germi, R., Effantin, G., & Grossi, L. “Three-dimensional structure of the Epstein–Barr virus capsid.” Journal of General Virology, vol.93, 2012, pp. 1769-1773.
  10. Sanchez, E. L., et al. “Viral activation of cellular metabolism.”Virology. 2015, pp. 479-480, pp. 609-618.
  11. Fujiwara, et al.“Humanized Mouse Models of Epstein-Barr Virus Infection and Associated Diseases.” Pathogens. 2013, pp.153–176.
  12. Crawford, D.H. “Biology and disease associations of Epstein-Barr virus.” Philosophical Transactions of the Royal Society of London Biology, 2001, pp. 356, pp. 461–473.
  13. Thompson,M., Kurzrock, R., “Epstein-Barr virus and cancer.” Clinical Cancer Research. vol.10, no. 3, 2004, pp. 803-821.
  14. Odumade, O. A., Hogquist, K. A., & Balfour, H. H. “Progress and Problems in Understanding and Managing Primary Epstein-Barr Virus Infections.” Clinical Microbiology Reviews, vol.24 no.1, 2011, pp. 193-209.
  15. Balandraud, N., Roudier, J., “Epstein-Barr virus and rheumatoid arthritis”. Joint Bone Spine. Vol.81, 2017.
  16. Shinozaki-Ushiku, A., Kunita, A., Fukayama, M., “Update on Epstein-Barr virus and gastric cancer.” International Journal of Oncology. 2015, pp.1421-1434.
  17. Cohen, J., Fauci, A., Varmus, H., Nabel, G., “Epstein-Barr virus: an important vaccine target for cancer prevention.” Science Translational Medicine. vol.3, no.107, 2011, pp. 107-108.