Sequence analysis of EBV immediate-early gene BZLF1 and BRLF1 in lymphomas

Abstract

The immediate-early (IE) genes, BZLF1 and BRLF1, play an important role in switching Epstein-Barr virus from the latent to the lytic state. The functions of the two IE genes and their respective proteins: ZEBRA and Rta have been well studied, but little is known about their DNA coding sequence variations and disease association. In order to investigate the sequence variation patterns and elucidate their association with lymphomas, BZLF1 and BRLF1 were analyzed in 26 and 33 lymphomas using PCR-direct sequencing method respectively. Three sequence variation types of BZLF1 gene were identified. The type BZLF1-A and BZLF1-B was detected in 34.6% (9/26) and 57.7% (15/26) of the tumor specimens, respectively. Among the three functional domains of ZEBRA, the transactivation domain had the most mutations. Three variation types were also identified in BRLF1 gene where type BR1-A and BR1-C were detected in 27.3% (9/33) and 69.7% (23/33) of specimens, respectively. Among the three functional domains of Rta, the dimerization domain was well conserved while multiple mutations were detected in both the DNA binding domain and the transactivation domain. The variation types BZLF1-B and BR1-C were more frequent in the lymphomas, compared with the throat washing samples from the healthy donors. These results suggest that the type BZLF1-B and BR1-C may be associated with the tumorigenesis of lymphoma.

T Cell Epitope Clustering in the Highly Immunogenic BZLF1 Antigen of Epstein-Barr Virus

“…An example of this is the Gln residue at position 195 of BZLF1, which is included within four epitopes restricted by either HLA-A30, -B7, -B8, or -Cw6. Importantly, the Gln residue is mutated to a charged His residue in type 2 EBV strains and the dominant type 1 EBV strains in China (32). Since HLA-Cw6 is expressed at a high frequency in parts of China, we examined the impact of this sequence polymorphism on recognition by HLACw6-restricted T cells raised against the 189 CRAKFKQLL 197 epitope.…”

Epstein–Barr Virus Strain Variation

“…Variation in the BZLF1 dimerisation sequence was studied using synthetic peptides but found to have only a small effect on its activity (Hicks et al 2001). Polymorphism has also been noted in BRLF1 Yang et al 2014), the EBV transcription factor which cooperates with BZLF1 to activate the early lytic cycle genes. Although a possible disease association was noted, this would require substantiation with more samples and controls.…”

“…There has been considerable interest in BZLF1 variants that might affect its function or expression (Lorenzetti et al 2012;Jin et al 2010;Imajoh et al 2012;Yang et al 2014). Although there are suggestions of variant sequence in Zp correlating with disease (Martini et al 2007;Lorenzetti et al 2014), further functional analysis would be required to substantiate this.…”

Epstein Barr Virus Volume 1

“…Variation in the BZLF1 dimerisation sequence was studied using synthetic peptides but found to have only a small effect on its activity (Hicks et al 2001). Polymorphism has also been noted in BRLF1 (Jia et al 2010;Yang et al 2014), the EBV transcription factor which cooperates with BZLF1 to activate the early lytic cycle genes. Although a possible disease association was noted, this would require substantiation with more samples and controls.…”

“…There has been considerable interest in BZLF1 variants that might affect its function or expression (Lorenzetti et al 2012;Jin et al 2010;Imajoh et al 2012;Yang et al 2014). There has been considerable interest in BZLF1 variants that might affect its function or expression (Lorenzetti et al 2012;Jin et al 2010;Imajoh et al 2012;Yang et al 2014).…”