Feedback Loop Regulation between Pim Kinases and Tax Keeps Human T-Cell Leukemia Virus Type 1 Viral Replication in Check

Abstract

The Pim family of serine/threonine kinases promote tumorigenesis by enhancing cell survival and inhibiting apoptosis. Three isoforms exist, Pim-1, -2, and -3, that are highly expressed in hematological cancers, including Pim-1 in adult T-cell leukemia (ATL). Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of ATL, a dismal lymphoproliferative disease known as adult T-cell leukemia. The HTLV-1 virally encoded oncogene Tax promotes CD4+ T-cell transformation through disruption of DNA repair pathways and activation of survival and cellular proliferation pathways. In this study, we found Tax increases the expression of Pim-1 and Pim-3, while decreasing Pim-2 expression. Furthermore, we discovered that Pim-1, -2, and -3 bind Tax protein to reduce its expression thereby creating a feedback regulatory loop between these two oncogenes. The loss of Tax expression triggered by Pim kinases led to loss in Tax-mediated transactivation of the HTLV-1 long terminal repeat (LTR) and reductions in HTLV-1 virus replication. Because Tax is also the immunodominant cytotoxic T cell lymphocytes (CTL) target, our data suggest that Pim kinases may play an important role in immune escape of HTLV-1-infected cells. IMPORTANCE The Pim family of protein kinases have established pro-oncogenic functions. They are often upregulated in cancer; especially leukemias and lymphomas. In addition, a role for Pim kinases in control of virus expression and viral latency is important for Kaposi sarcoma-associated herpesvirus (KSHV) and human immunodeficiency virus type 1 (HIV-1). Our data demonstrate that HTLV-1 encodes viral genes that promote and maintain Pim kinase activation, which in turn may stimulate T-cell transformation and maintain ATL leukemic cell growth. HTLV-1 Tax increases expression of Pim-1 and Pim-3, while decreasing expression of Pim-2. In ATL cells, Pim expression is maintained through extended protein half-life and heat shock protection. In addition, we found that Pim kinases have a new role during HTLV-1 infection. Pim-1, -2, and -3 can subvert Tax expression and HTLV-1 virus production. This may lead to partial suppression of the host immunogenic responses to Tax and favor immune escape of HTLV-1-infected cells. Therefore, Pim kinases have not only pro-oncogenic roles but also favor persistence of the virus-infected cell.