Why is Epstein-Barr virus (EBV) associated with latent infection and expression of some (but not all) viral genes in B (B cell) lymphocytes clinically?

From the Guidelines

Epstein-Barr virus (EBV) establishes latent infection in B lymphocytes as a key survival strategy that allows the virus to persist in the host for life while evading immune detection, and this is clinically significant because it minimizes viral antigen presentation to the immune system while still maintaining viral persistence in memory B cells. During latency, EBV expresses only a limited subset of viral genes—primarily EBNAs (Epstein-Barr Nuclear Antigens), LMPs (Latent Membrane Proteins), and non-coding RNAs like EBERs—rather than its full genome 1. The specific latency programs (types I, II, and III) determine which viral genes are expressed and are associated with different EBV-related diseases. For example, Burkitt lymphoma typically shows type I latency (EBNA-1 only), while post-transplant lymphoproliferative disorders often display type III latency (all latent proteins) 1.

This selective gene expression allows EBV to transform B cells, promote their survival, and drive lymphoproliferation while remaining largely hidden from immune surveillance. Understanding these latency patterns is essential for diagnosing EBV-associated malignancies and developing targeted therapies against specific viral proteins expressed during latent infection. The expression of these latent proteins and RNAs differs in each EBV-associated disease at tissue levels, with only EBNA-1 and EBERs expressed in EBV genome-positive BL (latency I), and EBNA-1, EBERs, and LMPs generally expressed in cases with EBV genome-positive NPC, Hodgkin disease (HD), or T-cell or NK-cell lymphoma (latency II) 1.

In the context of immunocompromised patients, such as those with congenital or acquired immunodeficiency, EBV is associated with lymphoproliferative disease, and increases in EBV viral load detected by NAAT in peripheral blood may be present in patients before the development of EBV-associated lymphoproliferative disease 1. The diagnosis of EBV-associated lymphoproliferative disease requires demonstration of EBV DNA, RNA or protein in biopsy tissue.

Key points to consider in the clinical management of EBV-associated diseases include:

• The use of EBV serologic tests to diagnose EBV infection, with high IgG antibody titers against EBV VCA and EA in patients with chronic active EBV infection 1
• The role of NAAT in detecting EBV DNA in peripheral blood and tissues, and in monitoring EBV viral load in immunocompromised patients 1
• The importance of understanding the latency patterns of EBV in different diseases, and the expression of specific viral proteins and RNAs in these diseases 1
• The need for targeted therapies against specific viral proteins expressed during latent infection, and for the development of effective treatments for EBV-associated malignancies.

From the Research

Epstein-Barr Virus and Latent Infection

• Epstein-Barr virus (EBV) is associated with latent infection and expression of some (but not all) viral genes in B lymphocytes, which is a key aspect of its lifecycle 2, 3.
• During latent infection, EBV expresses a limited set of viral genes, including those involved in immune evasion and latency maintenance 4, 5.
• The expression of these latent genes allows EBV to evade the host immune system and establish a lifelong infection in B lymphocytes 2, 6.

Clinical Implications

• The latent infection of B lymphocytes by EBV is associated with various clinical manifestations, including infectious mononucleosis and EBV-associated malignancies such as lymphomas and nasopharyngeal carcinoma 3, 6.
• The expression of viral antigens in malignant cells makes them suitable targets for immunotherapeutic approaches, such as adoptive cell therapy with EBV-specific T cells 4.
• The interplay between EBV and the immune system is complex, and a better understanding of this relationship is crucial for the development of effective treatments for EBV-related disorders 4, 5.

Viral Gene Expression

• The early events in primary human B cells infected with EBV involve the transient expression of viral lytic genes, which contribute to the initial survival and cell cycle entry of resting B cells 5.
• The expression of latent genes, including those encoding nuclear antigens and latent membrane proteins, is essential for the maintenance of latency and the evasion of the host immune system 2, 6.
• The different patterns of expression of these latent genes determine the occurrence of different types of latency in the pathogenesis of particular malignancies 6.