Human T-cell lymphotropic virus type 1 p12I enhances interleukin-2 production during T-cell activation.

in Journal of virology by Wei Ding, Seung-Jae Kim, Amrithraj M Nair, Bindhu Michael, Kathleen Boris-Lawrie, Adam Tripp, Gerold Feuer, Michael D Lairmore

TLDR

  • The study investigates how a protein called p12(I) helps a virus called HTLV-1 infect and replicate in cells. The study found that p12(I) helps activate a protein called NFAT, which is important for the virus to establish a persistent infection in vivo and for infection in quiescent primary lymphocytes in vitro. The study also found that p12(I) needs to be in a specific part of the cell called the endoplasmic reticulum (ER) to activate NFAT. The study suggests that p12(I) could be a potential target for treating a disease called adult T-cell leukemia/lymphoma (ATLL), which is caused by HTLV-1.

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL) and a variety of lymphoproliferative disorders. The early virus-cell interactions that determine a productive infection remain unclear. However, it is well recognized that T-cell activation is required for effective retroviral integration into the host cell genome and subsequent viral replication. The HTLV-1 pX open reading frame I encoding protein, p12(I), is critical for the virus to establish persistent infection in vivo and for infection in quiescent primary lymphocytes in vitro. p12(I) localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus, increases intracellular calcium and activates nuclear factor of activated T cells (NFAT)-mediated transcription. To clarify the function of p12(I), we tested the production of IL-2 from Jurkat T cells and peripheral blood mononuclear cells (PBMC) expressing p12(I). Lentiviral vector expressed p12(I) in Jurkat T cells enhanced interleukin-2 (IL-2) production in a calcium pathway-dependent manner during T-cell receptor (TCR) stimulation. Expression of p12(I) also induced higher NFAT-mediated reporter gene activities during TCR stimulation in Jurkat T cells. In contrast, p12 expression in PBMC elicited increased IL-2 production in the presence of phorbal ester stimulation, but not during TCR stimulation. Finally, the requirement of ER localization for p12(I)-mediated NFAT activation was demonstrated and two positive regions and two negative regions in p12(I) were identified for the activation of this transcription factor by using p12(I) truncation mutants. These results are the first to indicate that HTLV-1, an etiologic agent associated with lymphoproliferative diseases, uses a conserved accessory protein to induce T-cell activation, an antecedent to efficient viral infection.

Overview

  • The study investigates the role of p12(I), a protein encoded by the HTLV-1 pX open reading frame I, in T-cell activation and viral infection. The study uses Jurkat T cells and peripheral blood mononuclear cells (PBMC) to test the effects of p12(I) on IL-2 production and NFAT-mediated transcription during T-cell receptor (TCR) stimulation. The study aims to clarify the function of p12(I) in T-cell activation and viral infection.

Comparative Analysis & Findings

  • The study found that lentiviral vector expressed p12(I) in Jurkat T cells enhanced IL-2 production in a calcium pathway-dependent manner during TCR stimulation. Expression of p12(I) also induced higher NFAT-mediated reporter gene activities during TCR stimulation in Jurkat T cells. In contrast, p12 expression in PBMC elicited increased IL-2 production in the presence of phorbal ester stimulation, but not during TCR stimulation. The study also demonstrated the requirement of ER localization for p12(I)-mediated NFAT activation and identified two positive regions and two negative regions in p12(I) for the activation of this transcription factor by using p12(I) truncation mutants.

Implications and Future Directions

  • The study's findings suggest that HTLV-1 uses a conserved accessory protein to induce T-cell activation, an antecedent to efficient viral infection. The study highlights the importance of understanding the early virus-cell interactions in determining a productive infection. Future research could explore the role of p12(I) in other lymphoproliferative disorders and investigate the potential of targeting p12(I) as a therapeutic approach for ATLL and other HTLV-1-associated diseases.
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