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. HIV infection is associated with EBV reactivation and an increase in EBV viral loads in saliva and blood, and people living with HIV frequently develop EBV-associated B-cell malignancies. In this study, we aimed to investigate the involvement of HIV-1 and EBV co-existence in the development of B-cell malignancies. To do so, we focused our attention on the two viral transcriptional activators (HIV-1 Tat and EBV Zta) and analyzed their possible interaction since they both have cell-penetration domains and can be found simultaneously in the blood or cells of people living with HIV. We investigated the interaction of Tat and Zta using co-immunoprecipitation, in vitro binding, YFP reconstitution assay and FRET. We found that they bind each other in human B cells and blood serum. Tat and Zta interaction was also observed in a serum sample from one HIV-positive individual. YFP reconstitution demonstrated that this interaction occurred predominantly in the nucleus, indicating that it might affect the host genome. We further analyzed the effects of Tat and Zta on primary and EBV-transformed human B cells by RNA-sequencing and found that the combined Tat and Zta action in B cells differed from a single action of the 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 the 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. Our findings suggest that the reduction of total HLA-ABC levels in B cells upon Tat and Zta interaction might be linked to HLA-ABC proteasomal degradation. Furthermore, HLA-ABC downregulation induced by Tat and Zta interaction conferred protection against cytotoxic T cell recognition of EBV-infected B cells. To conclude, we demonstrated for the first time that HIV-1 Tat and EBV Zta interacted directly in B cells and blood serum; this interaction can be found in people with HIV. This interaction brings about immune evasion of EBV-infected or transformed B cells.