The Role of Viral Proteins in Epstein-Barr Virus Induced Disease

Introduction

Figure 1. The original electron micrographs of cultured Burkits Lymphoma tissue published by Epstein and Barr in 1964. V denotes the presence of EBV virions. [1].

The Epstein-Barr Virus (EBV) is a common human herpes virus that can cause both infectious mononucleosis and lymphoproliferative disease. EBV is unique in that it infects about 95% of the adult population between 35-40 years old in the U.S. [1]. EBV is associated with cancers such as Burkitt’s Lymphoma and nasopharyngeal carcinoma [1,2]. The virus is capable of infecting host B-cells, and primarily proliferates via a non-lytic mechanism [2]. During this latent process, virus-derived nuclear proteins (EBNAs) and membrane proteins (LMPs) are expressed by infected host cells [2]. An advancing area of research is aimed at understanding how viral proteins may play a role in lymphoproliferative disease. LMP-1 is one of these viral membranous proteins that may induce indefinite, tumorigenic replication in infected B-cells [2,3]. In a sense, the LMP-1 acts to "transform" these B-cells into an immortalized, proliferating line. While EBV infections usually only cause mild symptoms, attempts to develop treatments and antivirals have generally been unsuccessful [1]. It is particularly difficult to control spread between hosts as chronic infections may reactivate, allowing symptom-free carriers to continue to transmit the virus years after initial infection [1]. Due to EBV's putative role in carcinogenesis and the limited success in development of antivirals to combat infection, it is essential to develop a deeper understanding of the mechanisms by which the virus alters the character of host cells.

Virus Classification and Genome

The Epstein-Barr virus is a Baltimore Class I virus of the family Herpesviridae. It is a gammaretrovirus also designated as Human Herpes Virus 4 (HHV-4). M.A. Epstein and Yvonne Barr were the first identify EBV in tumor tissue associated with Burkitt's Lymphoma. The researchers used electron microscopy to determine that these viral particles were very similar in structure to Herpes simplex virions [4]. The genome of EBV is composed of double-stranded DNA and is 172,282 base-pairs long [5]. This relatively long genome is characteristic of Herpes viruses; Herpes simplex has a 152-kilobase genome [6].

EBV Virion Structure

Figure 2. A general diagram of a herpesvirus virion. Note that the dsDNA genome is wrapped around a central nucleo-protein. Spike glycoproteins on the surface play a role in host cell entry. [2].

Epstein and Barr observed that this lymphoma-associated virus was about 20% smaller than typical Herpes simplex virions [4]. Similar to other Herpesviruses, the innermost part of the EBV virion consists of DNA wrapped around a central nucleo-protein core [7]. The core of the virion is surrounded by a nucleocapsid, a layer of protein tegument, and finally and outer envelope with spike glycoproteins [7]. Similar to many other viruses, many of these glycoproteins are vital for host-cell entry mechanisms.

References

[1]"Epstein-Barr Virus and Infectious Mononucleosis." Centers for Disease Control. http://www.cdc.gov/ncidod/diseases/ebv.htm. Accessed: 11/3/12.

[2]Young LS,Rickinson AB. 2004. Epstein-Barr Virus: 40 Years On. Nature Reviews. 4:757-768.

[3]Wang D, Liebowitz D, Kieff E. 1985. An EBV Membrane Protein Expressed in Immortalized Lymphocytes Transforms Established Rodent Cells. Cell. 43: 831-840.

[4]Epstein MA, Achong BG, Barr YM. 1964. Virus Particles In Cultured Lymphoblasts from Burkitt's Lymphoma. The Lancet. 283:702-703.

[5] Baer R, Bankier AT, Biggin MD, Deininger DL, Farrell PJ, Gibson TJ, Hatfull G, Hudson GS, Satchwell SC, Seguin C, Tuffnell PS, Barrell BG. 1984. DNA sequence and expression of the B95-8 Epstein-Barr Virus Genome. Nature. 310: 207-211.

[6] Mahiet C, Ergani A, Huot N, Alende N, Azough A, Salvaire F, Bensimon A, Conseiller E, Wain-Hobson S, Labetoulle M, Berradeau S. 2012. Structural Variability of the Herpes Simplex Virus 1 Genome in Vitro and In Vivo. Journal of Virology. 86(16): 8592-8601.

[7]Liebowitz D, Kieff E. 1993. Epstein-Barr virus. In: The Human Herpesvirus. Roizman B, Whitley RJ, Lopez C, editors. New York. 107–172.