INVESTIGATING EPSTEIN-BARR VIRUS INTRASPECIES DIVERSITY AND IDENTIFYING VIRAL GENOVARIANTS ASSOCIATED WITH MALIGNANCIES DEVELOPMENT



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Abstract

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus linked to development of specific malignancies. EBV latent membrane protein 1 (LMP-1) encoded by LMP-1 gene markedly contributes to EBV-related transforming potential. The 3′-end of LMP-1 gene, corresponding to the C-terminal region of the relevant protein, encodes three functional domains involved in the regulation of cell proliferation, survival of infected cells, recognition of viral antigens by immune cells, and, consequently, EBV transforming activity. Molecular genetic polymorphism of this region underlies a widely used EBV-specific intraspecies classification. It seems plausible to further refine and expand current classification required to identify novel EBV genovariants, including those associated with malignancy. 1,113 nucleotide sequences of EBV LMP-1 gene 3′-terminal fragment deposited in the NCBI Nucleotide database were analyzed. Based on signature substitutions, sequences were assigned to variant groups according to intraspecies classification proposed by Edwards et al. (1999). Within each variant, genovariants were identified according to characteristic nucleotide substitutions and minimal pairwise p-distances. 23 EBV genovariants were identified. Classification accuracy was evaluated using within-group and between-group p-distances, whereas reproducibility was assessed by comparing phylogenetic trees with tanglegram-based analysis. It was found out that B95-8 / Q, Med / EGE, Med / L, NC / GP and Alaskan / T dominated in Russian Federation population. Recombinant origin was confirmed for B95-8 / N genovariant. Associations between EBV genovariant and malignancy were investigated for nasopharyngeal carcinoma in Chinese population, Burkitt lymphoma in Kenyan population, Hodgkin lymphoma in Brazilian population, and T-cell lymphoma in Japanese population. Carriage of the following genovariants was associated with increased odds of developing: nasopharyngeal carcinoma in Chinese population – for China 1 / HEED genovariant with G167859A nt (G335D aa) substitution; Burkitt lymphoma in Kenyan population – for China 1 / NQEG genovariant with substitution C168226A nt (H213N aa). No associations with specific EBV genovariants were identified for Hodgkin lymphoma or T-cell lymphoma. Likewise, no association was observed between odds of studied malignancies and quantity of tandem 33-nt (11-aa) repeats, the presence of either 15-nt (5-aa) insertion or 30-nt (10-aa) deletion in viral sequence.

About the authors

Elena N. Filatova

Blokhina Scientific Research Institute of Epidemiology and Microbiology of Nizhny Novgorod

Email: el.filatova83@mail.ru
ORCID iD: 0000-0002-6683-7191
SPIN-code: 1986-8147

Candidate of Sciences in Biology, leading researcher

 

Russian Federation

Oleg V. Utkin

Blokhina Scientific Research Institute of Epidemiology and Microbiology of Nizhny Novgorod

Email: utkino2004@mail.ru
ORCID iD: 0000-0002-7571-525X
SPIN-code: 1174-6500

PhD (Biology), Head of Laboratory of Molecular Biology and Biotechnology

Russian Federation, 603950, Nizhny Novgorod, Malaya Yamskaya st., 71

Sergey P. Dmitriev

Research Institute of Clinical Oncology "Nizhny Novgorod Regional Clinical Oncological Dispensary"

Email: sergei-fcsm@yandex.ru
ORCID iD: 0009-0008-1051-882X
SPIN-code: 5107-4997

head of the 9th oncology department

Russian Federation, 603063, Russia, Nizhny Novgorod, Delovaya st., 11/1

Sergey V. Gamayunov

Research Institute of Clinical Oncology "Nizhny Novgorod Regional Clinical Oncological Dispensary"

Author for correspondence.
Email: sgamajnovs@mail.ru
ORCID iD: 0000-0002-0223-0753
SPIN-code: 9828-9522

Doctor of Science in Medical Sciences, Professor, Head Physician

Russian Federation, 603063, Russia, Nizhny Novgorod, Delovaya st., 11/1

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