HIV-1 Tat Activates Akt/mTORC1 Pathway and AICDA Expression by Downregulating Its Transcriptional Inhibitors in B Cells.

Burkitkan Akbay,Amangeldy K Bissenbaev,Yegor Vassetzky,Svetlana Dokudovskaya,Diego Germini,Evgeny V Sheval,Yana R Musinova

doi:10.3390/ijms22041588

Abstract

HIV-1 infects T cells, but the most frequent AIDS-related lymphomas are of B-cell origin. Molecular mechanisms of HIV-1-induced oncogenic transformation of B cells remain largely unknown. HIV-1 Tat protein may participate in this process by penetrating and regulating gene expression in B cells. Both immune and cancer cells can reprogram communications between extracellular signals and intracellular signaling pathways via the Akt/mTORC1 pathway, which plays a key role in the cellular response to various stimuli including viral infection. Here, we investigated the role of HIV-1 Tat on the modulation of the Akt/mTORC1 pathway in B cells. We found that HIV-1 Tat activated the Akt/mTORC1 signaling pathway; this leads to aberrant activation of activation-induced cytidine deaminase (AICDA) due to inhibition of the AICDA transcriptional repressors c-Myb and E2F8. These perturbations may ultimately lead to an increased genomic instability and proliferation that might cause B cell malignancies.

Highlights

IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
We hypothesized that Tat could modulate the Akt/mTORC1 pathway in B cells, and here, we demonstrated that in B cells, HIV-1 Tat induced reactive oxygen species (ROS) production and DNA damage, and activates the Akt/mTORC1 pathway, resulting in activation-induced cytidine deaminase (AICDA) overexpression via mTORC1-dependent inhibition of AICDA repressors c-Myb and E2F8
We have previously demonstrated that AICDA transcription was induced in B cells from healthy donors incubated with HIV-1 Tat and in B cells from HIV-patients, yet how this activation occurs was not clear [38]. mTORC1 positively regulates AICDA expression [42]; we hypothesized that HIV-1 Tat-induced AICDA transcription in B cells is dependent on the mTORC1 pathway

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. HIV-1 trans-activator of transcription (Tat) is one of the key viral regulatory proteins essential for HIV-1 replication, establishment of infection and virus reactivation [1,2]. Tat is a small protein of 86–102 amino acids (depending on the viral strain) with a predicted molecular weight of 14–16 kDa. HIV-1 predominantly infects T cells and macrophages, and. Tat is expressed in productively infected cells. Tat can be released from infected cells into blood, where it can penetrate many cell types due to its protein transduction domain [3,4,5,6]

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