Epstein-Barr Virus Isolates Retain Their Capacity To Evade T Cell Immunity through BNLF2a despite Extensive Sequence Variation

Abstract

The Epstein-Barr virus (EBV)-encoded immune evasion protein BNLF2a inhibits the transporter associated with antigen processing (TAP), thereby downregulating HLA class I expression at the cell surface. As a consequence, recognition of EBV-infected cells by cytotoxic T cells is impaired. Here, we show that sequence polymorphism of the BNLF2a protein is observed with natural EBV isolates, with evidence for positive selection. Despite these mutations, the BNLF2a variants efficiently reduce cell surface HLA class I levels. This conservation of BNLF2a function during evolution of EBV implies an important role for the viral TAP inhibitor in preventing T cell recognition during viral infection.

Sequence analysis of EBV immune evasion gene BNLF2a in EBV associated tumors and healthy individuals from nasopharyngeal carcinoma endemic and non‐endemic regions of China

“…The mutation at position 8 or 40 alone was relatively less frequent, especially at 8. This was consistent with a previous study [Horst et al, ]. We speculated that position 8 and 40 may be related on the spatial structure or during the function process.…”

“…Its specific mechanism remains unclear, Wycisk, A. I. et al [Wycisk et al, ] illustrated that BNLF2a can prevent a conformational change of TAP induced by peptide binding. Compared to wild‐type BNLF2a, a histidine‐to‐proline substitution at position 3 impaired its ability to reduce HLA I cell surface levels [Horst et al, ]. Thus, the position 3 may be a critical site for its function.…”

Epstein–Barr Virus Strain Variation

“…Variation has also been reported in the early lytic cycle genes BHRF1 ) and BNLF2a (Horst et al 2012). BHRF1 is similar to BCL2 with antiapoptosis activity and BNLF2a has a role in immune evasion, reducing cell surface HLA class I levels.…”

“…Evidence for positive selection also comes from ratios of non-synonymous to synonymous changes in the SNPs present in reading frames (Palser et al 2015). This showed an excess of non-synonymous changes in EBNA3 genes and LMP1, as predicted from the immunological studies, but also in the immune evasion protein BNLF2a (Horst et al 2012), which binds TAP and in the glycoproteins gp350 (BLLF1) and gL (BKRF2). So far little is known about the extent to which EBV selection in vivo may be affected by other polymorphisms that could affect, for example, ability to promote cell proliferation or viral replication.…”

Immune control of oncogenic γ-herpesviruses

“…In order to persist, EBV employs a variety of immune escape mechanisms against these comprehensive T cell responses, and the main strategies differ between latent and lytic EBV infection [34] (Figure 1). During latent infection EBV protein down-regulation is the main strategy.…”