Summary auto-generated
This study examined sequence variations in EBNA-1, a viral protein essential for Epstein-Barr virus (EBV) persistence, to understand how EBV establishes different tissue tropisms and associations with cancers. The researchers analyzed EBNA-1 sequences from peripheral blood lymphocytes (PBLs) and oral secretions (saliva) of 53 normal seropositive individuals, as well as from nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma (BL) tumor samples. They identified five EBV subtypes based on EBNA-1 carboxy-terminal sequences: two prototypes (P-ala and P-thr) and three variants (V-pro, V-leu, and V-val). The key finding was that different subtypes showed distinct tissue distributions: the prototype P-ala dominated in normal lymphocytes (75% of individuals) but was rarely found in tumors; V-pro was restricted to PBLs and associated with a mutated version in BL; and V-val was detected in saliva but not PBLs, and was associated with NPC. The findings suggest EBNA-1 sequence variations influence cellular tropism and may determine EBV's ability to persist in different cell types, potentially affecting oncogenic potential.
Key findings
- EBV exists as multiple EBNA-1 subtypes (P-ala, P-thr, V-pro, V-leu, V-val) in normal individuals, with over half carrying multiple subtypes simultaneously
- The prototype EBNA-1 (P-ala) is prevalent in normal individuals (75%) but is rarely found in EBV-associated tumors, while variant subtypes show strong tumor associations
- V-val EBNA-1 is detected in oral secretions but not peripheral blood lymphocytes, suggesting epithelial cell tropism and association with nasopharyngeal carcinoma
- V-pro is restricted to peripheral blood and never found in isolation, while a mutated version appears in Burkitt's lymphoma but not nasopharyngeal carcinoma
- EBNA-1 sequence variations correlate with distinct tissue distributions and oncogenic associations, suggesting the protein directly influences viral tropism and transformation potential
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Abstract
In seropositive individuals Epstein-Barr virus (EBV) establishes a virus reservoir in peripheral blood lymphocytes (PBLs). Transmission from one individual to another occurs via saliva due to a lytic (virion productive) phase of infection in the oropharynx. EBNA-1 is responsible for maintaining viral episomes in the host cell and could, therefore, also affect the persistence of the virus in different cell lineages. Based on sequence analysis of EBNA-1 we now demonstrate that (i) in addition to the prototype EBNA-1 (identical to the B95.8 virus EBNA-1), EBV in normal individuals encompasses multiple EBNA-1 subtypes, both in PBLs and in oral secretions; (ii) although EBV with prototype EBNA-1 is the predominant virus in normal individuals, it is very rarely associated with either nasopharyngeal carcinoma (NPC) or Burkitt's lymphoma (BL); (iii) EBV with an EBNA-1 subtype (V-val) frequently associated with NPC is also selectively detected in oral secretions and not in PBLs; (iv) EBV with the EBNA-1 subtype V-pro is restricted to PBLs, while a mutated version of this subtype is present in BL, but not in NPC. These findings suggest that the variations in EBNA-1 may be relevant to the ability of EBV to persist in different cell types, and hence relevant to its oncogenic potential.