Interaction between HIV-1 Tat and EBV Zta favours immune escape of B cells by downregulating HLA-ABC expression

Both Human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) are associated with an increased risk of malignancies. People living with HIV frequently have EBV reactivation and develop EBV-associated B-cell malignancies. In this study, we aimed to uncover the involvement of HIV-1 and EBV co-existence in the development of B-cell malignancies. We studied two viral transcriptional activators (HIV-1 Tat and EBV Zta) and their possible interaction since they both have cell-penetration domains and can be found simultaneously in the blood or cells of people with HIV. We found that Tat and Zta directly bound each other in human B cells, T cells, and blood serum. Using RNA-sequencing, we found that combined Tat and Zta action in B cells differed from a simple combination of two proteins. A subset of genes, activated by Tat or Zta alone, that trigger an immune response and antigen presentation in B cells, remained unchanged when two proteins were combined. B cells, treated or transfected with Tat and Zta, exhibited a substantial decrease in HLA-ABC (MHC class I) expression, a critical component of the antigen processing and presentation pathway. HLA-ABC downregulation induced by Tat and Zta interaction conferred protection against cytotoxic T cell recognition of EBV-infected B cells. Tat and Zta interaction was also observed in serum from an HIV-positive individual. To conclude, we demonstrated for the first time the direct interaction between HIV-1 Tat and EBV Zta; this interaction can bring about immune evasion of EBV-infected or transformed B cells.