ИСТИНА

Both Human immunodeficiency virus (HIV) and Epstein Barr Virus (EBV) are associated with an increased risk of malignancies. Infection with EBV is highly widespread (90% of population). In people living with HIV (PLWH), HIV infection reactivates EBV and increases EBV viral loads in saliva and blood. Both viruses encode for ubiquitous transcriptional activator proteins, essential for the pathogenesis of infection and associated malignancies: Tat protein of HIV-1 and Zta protein of EBV. They possess many similar features: they can exit infected cells, penetrate other cells and regulate viral and host gene transcription. We hypothesized that since Tat and Zta can be found simultaneously in blood or cells of PLWH, they could interact physically and/or functionally with each other. We first investigated the interaction of two viral proteins using co-immunoprecipitation and found that Tat and Zta interact with each other in human B cells (RPMI8866 line), T cells (Jurkat line) and blood serum. Tat and Zta interaction was also observed in a serum sample from a HIV-infected patient. Using in vitro binding assay, we next found that this interaction doesn’t require additional protein partners and has a Kd ~ 0.11 μM. YFP reconstitution assay demonstrated that this interaction occurred predominantly in the cell nucleus, indicating that it might affect the host genome. We further analyzed the effects of Tat and Zta on primary human B cells’ transcriptome by RNA-sequencing and found that combined Tat and Zta action in B cells differed from a simple combination of two proteins. Additionally, Tat and Zta combination only, but not single protein action, induced several specific genes. These data indicate that Tat and Zta interaction may have a functional significance in HIV/EBV co- or super-infection. In summary, we demonstrated for the first time that HIV-1 Tat and EBV Zta interacted directly in B, T cells and blood serum; this interaction can be found in PLWH and it modifies the expression of host genes. This research was funded by the IDB RAS Government basic research program 0088-2021-0007.