Characterization of variants in the promoter of EBV gene BZLF1 in normal donors, HIV-positive patients and in AIDS-related lymphomas.
OBJECTIVE
The aim of this study was to determine the occurrence of polymorphic variants of EBV BamHI fragment Z (BZLF1) promoter zone Zp in tumor and non-tumor-associated EBV. We characterized the Zp region in type A and type B EBV, infecting AIDS-related non-Hodgkin's lymphomas (AIDS-NHL) and non-malignant lymphoid tissues derived from HIV-positive patients and from healthy individuals.


METHODS
The Zp region was directly sequenced in 133 EBV-positive DNA samples: 63 AIDS-NHL (32 systemic AIDS-NHL and 31 AIDS-primary central nervous system lymphoma [AIDS-PCNSL]), 30 lymphoid tissues derived from HIV-positive individuals and 40 lymphoid samples derived from healthy individuals. The chi square test was used to assess for statistically significant differences among proportions, and a two-tailed P value </=0.05 was chosen as statistically significant.


RESULTS
We found three polymorphic Zp variants: Zp-P, considered to be the prototype sequence; Zp-V3, that differs from Zp-P for three nucleotide substitutions; and a new variant, Zp-PV, that differs from Zp-P for a single nucleotide substitution. Zp-V3 was significantly associated with AIDS-PCNSL (P<0.001) and with systemic AIDS-NHL (P=0.007), in particular with AIDS-related immunoblastic lymphoma (P<0.001). Moreover, in malignant samples, this variant was also significantly associated with type B EBV (P<0.001). Finally, the new identified Zp-PV variant was isolated in 7 AIDS-PCNSL.


CONCLUSIONS
The frequency of polymorphisms in the regulatory zone of BZLF1 is different between malignant and non-malignant samples in AIDS patients and may identify EBV subtypes with different transforming activities, including those associated to the pathogenesis of B cell lymphoma.
Martini
Maurizio
M
Institute of Pathological Anatomy, Catholic University of Rome, School of Medicine, Largo Francesco Vito 1, 00168 Rome, Italy. labpatmol@rm.unicatt.it <labpatmol@rm.unicatt.it>
Capello
Daniela
D
Serraino
Diego
D
Navarra
Assunta
A
Pierconti
Francesco
F
Cenci
Tonia
T
Gaidano
Gianluca
G
Larocca
Luigi Maria
LM
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000821:virology*; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D020031:Epstein-Barr Virus Infections / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008221:Lymphoid Tissue / Q000821:virology; D008223:Lymphoma / Q000821:virology*; D016483:Lymphoma, AIDS-Related / Q000821:virology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D013223:Statistics as Topic; D015534:Trans-Activators / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*
C063676:BZLF1 protein, Herpesvirus 4, Human; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D015534:Trans-Activators; D014764:Viral Proteins