Interplay between innate immunity and the viral oncoproteins Tax and HBZ in the pathogenesis and therapeutic response of HTLV-1 associated adult T cell leukemia

Abstract

The Human T-cell Leukemia virus type 1 (HTLV-1) causes an array of pathologies, the most aggressive of which is adult T-cell leukemia (ATL), a fatal blood malignancy with dismal prognosis. The progression of these diseases is partly ascribed to the failure of the immune system in controlling the spread of virally infected cells. HTLV-1 infected subjects, whether asymptomatic carriers or symptomatic patients are prone to opportunistic infections. An increasing body of literature emphasizes the interplay between HTLV-1, its associated pathologies, and the pivotal role of the host innate and adoptive immune system, in shaping the progression of HTLV-1 associated diseases and their response to therapy. In this review, we will describe the modalities adopted by the malignant ATL cells to subvert the host innate immune response with emphasis on the role of the two viral oncoproteins Tax and HBZ in this process. We will also provide a comprehensive overview on the function of innate immunity in the therapeutic response to chemotherapy, anti-viral or targeted therapies in the pre-clinical and clinical settings.

Retroviral b‐Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation

“…A recent study showed differences in the cytoplasmic presence of HBZ protein in infected T cells from asymptomatic (AC) and HAM/TSP patients contrary to what's known for ATLL cells, where it is retained primarily in the nucleus (Yasuma et al, 2016). Interestingly, HBZ was found to be accumulated in the nucleus of OSP2 cells while also maintaining its presence in the cytoplasm Furthermore, we cannot disregard the part Tax may be playing in OPS2 cells, given it is role modulating IFN and NFkB responses (Hajj & Bazarbachi, 2022). We postulate a model describing the activities of HBZ that could enlighten the mechanism of observed HBZ-mediated effects (Figure 7e).…”

“…The cellular localization of HBZ in these two cell systems may be impacting the different observations we see between ATL‐like and HAM/TSP‐like systems. Furthermore, we cannot disregard the part Tax may be playing in OPS2 cells, given it is role modulating IFN and NFkB responses (Hajj & Bazarbachi, 2022 ). We postulate a model describing the activities of HBZ that could enlighten the mechanism of observed HBZ‐mediated effects (Figure 7e ).…”

Reprogramming of pyrimidine nucleotide metabolism supports vigorous cell proliferation of normal and malignant T cells

“… 1 , 2 It takes several decades for HTLV-1 carriers to develop ATL. During ATL leukemogenesis, HTLV-1–infected T cells (ATL cells) acquire growth advantages through several mechanisms, including induction of viral oncoproteins 3 and accumulation of genetic 4 , 5 or epigenetic abnormalities, 6 leading to disease development and progression from indolent ATL (consisting of smoldering and chronic types) to aggressive ATL (consisting of acute and lymphoma types). Several proteins are differentially expressed by HTLV-1–infected cells and ATL cells and are thought to be molecular targets for the treatment and diagnosis of ATL.…”

IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors

“…The cumulative risks for ATL development among HTLV-1 carriers are estimated at approximately 5% (1,2). The initial expansion of HTLV-I infected cells is driven by the viral oncoprotein Tax, which activates transcription of the proviral genome from the proviral promoter and induces T-cell autocrine loops of IL-2, IL-15, and their respective receptors through Tax-I-kBa kinase axis (3). Tax alters functions of many transcription factors including CREB/ATF, AP-1, and NF-kB to upregulate growth as well as anti-apoptotic signals and represses p53, DNA polymerase beta, PCNA, and MAD-1 to interfere with multiple cell cycle regulatory and DNA repair systems (3).…”