Human T cell lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma (ATLL), a fetal malignant infection. Recently, HTLV-1 new asymptomatic carriers (ACs) have frequently been reported among blood donors. Reaching the profound concept of HTLV-1-associated molecular pathogenesis could result in finding novel therapeutic strategies. The current study aimed to determine leukemia-related signaling regulation in ATLL. Thirty participants were evaluated in 3 groups, including 10 ATLL patients, 10 ACs, and 10 normal controls. Blood samples were isolated without any chemotherapy history from ATLL patients. Also, blood samples were recovered from ACs and normal individuals. White blood cells isolation was done on the collected blood samples. After this, RNA was extracted from the prepared samples and used for the cDNA synthesis. TAX and HTLV-1 basic leucine zipper factor as viral genes and cellular genes, including MKP-1, EVI-1, JNK-1, FOXO-1, AKT-1, DEPTOR, MTOR, and JUN, were investigated using real-time PCR. The mean age of ATLL patients was 53.2 ± 7.32 years, and 9 (90%) were male. The EVI-1 and FOXO-1 expression levels were significantly associated with ATLL patients compared with the internal control. However, the significant differences in expression of other genes in the remaining groups were not seen. Discovering viral and cellular signaling pathways that regulate HTLV-1 transformation is essential. A novel therapeutic strategy for ATLL-regulating cellular signaling pathways in vivo could be considered. Therefore, clinical trials using activators and inhibitors of related cellular signaling pathways for cell therapy of ATLL are recommended. It is recommended that more investigation be conducted on FOXO-1 and EVI-1 to target these genes and reveal the molecular pathogenesis of ATLL.

Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-β/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

Human T-lymphotropic virus 1 (HTLV-1) is associated with the development of several pathologies and chronic infection in humans. The inefficiency of the available treatments and the challenge in developing a protective vaccine highlight the need to produce effective immunotherapeutic tools. The HTLV-1 basic leucine zipper (bZIP) factor (HBZ) plays an important role in the HTLV-1 persistence, conferring a survival advantage to infected cells by reducing the HTLV-1 proteins expression, allowing infected cells to evade immune surveillance, and enhancing cell proliferation leading to increased proviral load.
We have generated a recombinant Modified Virus Vaccinia Ankara (MVA-HBZ) and a plasmid DNA (pcDNA3.1(+)-HBZ) expressing a multiepitope protein based on peptides of HBZ to study the immunogenic potential of this viral-derived protein in BALB/c mice model. Mice were immunized in a prime-boost heterologous protocol and their splenocytes (T CD4+ and T CD8+) were immunophenotyped by flow cytometry and the humoral response was evaluated by ELISA using HBZ protein produced in prokaryotic vector as antigen.
T CD4+ and T CD8+ lymphocytes cells stimulated by HBZ-peptides (HBZ42-50 and HBZ157-176) showed polyfunctional double positive responses for TNF-α/IFN-γ, and TNF-α/IL-2. Moreover, T CD8+ cells presented a tendency in the activation of effector memory cells producing granzyme B (CD44+High/CD62L-Low), and the activation of Cytotoxic T Lymphocytes (CTLs) and cytotoxic responses in immunized mice were inferred through the production of granzyme B by effector memory T cells and the expression of CD107a by CD8+ T cells. The overall data is consistent with a directive and effector recall response, which may be able to operate actively in the elimination of HTLV-1-infected cells and, consequently, in the reduction of the proviral load. Sera from immunized mice, differently from those of control animals, showed IgG-anti-HBZ production by ELISA.
Our results highlight the potential of the HBZ multiepitope protein expressed from plasmid DNA and a poxviral vector as candidates for therapeutic vaccine.

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The human T-cell leukemia virus type 1 (HTLV-1) is the only known human oncogenic retrovirus. HTLV-1 can cause a type of cancer called adult T-cell leukemia/lymphoma (ATL). The virus is transmitted through the body fluids of infected individuals, primarily breast milk, blood, and semen. At least 5-10 million people in the world are infected with HTLV-1. In addition to ATL, HTLV-1 infection can also cause HTLV-I-associated myelopathy (HAM/TSP). ATL is characterized by a low viral expression and poor prognosis. The oncogenic mechanism triggered by HTLV-1 is extremely complex and the molecular pathways are not fully understood. However, viral regulatory proteins Tax and HTLV-1 bZIP factor (HBZ) have been shown to play key roles in the transformation of HTLV-1-infected T cells. Moreover, several studies have shown that the final fate of HTLV-1-infected transformed Tcell clones is the result of a complex interplay of HTLV-1 oncogenic protein expression with cellular transcription factors that subvert the cell cycle and disrupt regulated cell death, thereby exerting their transforming effects. This review provides updated information on the mechanisms underlying the transforming action of HTLV-1 and highlights potential therapeutic targets to combat ATL.

HTLV-1 is an oncogenic human retrovirus and the etiologic agent of the highly aggressive ATL malignancy. Two viral genes, Tax and Hbz, are individually linked to oncogenic transformation and play an important role in the pathogenic process. Consequently, regulation of HTLV-1 gene expression is a central feature in the viral lifecycle and directly contributes to its pathogenic potential. Herein, we identified the cellular transcription factor YBX1 as a binding partner for HBZ. We found YBX1 activated transcription and enhanced Tax-mediated transcription from the viral 5\' LTR promoter. Interestingly, YBX1 also interacted with Tax. shRNA-mediated loss of YBX1 decreased transcript and protein abundance of both Tax and HBZ in HTLV-1-transformed T-cell lines, as well as Tax association with the 5\' LTR. Conversely, YBX1 transcriptional activation of the 5\' LTR promoter was increased in the absence of HBZ. YBX1 was found to be associated with both the 5\' and 3\' LTRs in HTLV-1-transformed and ATL-derived T-cell lines. Together, these data suggest that YBX1 positively influences transcription from both the 5\' and 3\' promoter elements. YBX1 is able to interact with Tax and help recruit Tax to the 5\' LTR. However, through interactions with HBZ, YBX1 transcriptional activation of the 5\' LTR is repressed.

Adult T cell leukemia/lymphoma is a malignancy with a poor prognosis caused by human T lymphocyte virus type 1 (HTLV-1) infection. Tax and HBZ are two major viral proteins that may be involved in oncogenesis by disrupting apoptosis. Because Bcl-xL plays an integral role in the anti-apoptotic pathway, this study examines the interaction between host apoptosis and oncoproteins. We investigated 37 HTLV-1-infected individuals, including 18 asymptomatic and 19 adult T cell leukemia/lymphoma (ATLL) subjects. mRNA was extracted and converted to cDNA from peripheral blood mononuclear cells, and then gene expression was determined using TaqMan q-PCR. Moreover, the HTLV-1 proviral load (PVL) was also measured using a commercial absolute quantification kit (Novin Gene, Iran). Data analysis revealed that the mean of TAX, HBZ, and PVL was significantly higher among the study groups (ATLL and carrier groups p = .003, p = .000, and p = .002 respectively). There was no statistical difference in Bcl-xL gene expression between the study groups (p = .323). It is proposed that this anti-apoptotic pathway may not be directly involved in the development of ATLL lymphoma. Bcl-xL, TAX, HBZ gene expression, and PVL can be utilized as prognostic markers.

Adult T cell leukemia (ATL) is an aggressive hematologic disease caused by human T cell leukemia virus type 1 (HTLV-1) infection. Various animal models of HTLV-1 infection/ATL have been established to elucidate the pathogenesis of ATL and develop appropriate treatments. For analyses employing murine models, transgenic and immunodeficient mice are used because of the low infectivity of HTLV-1 in mice. Each mouse model has different characteristics that must be considered before use for different HTLV-1 research purposes. HTLV-1 Tax and HBZ transgenic mice spontaneously develop tumors, and the roles of both Tax and HBZ in cell transformation and tumor growth have been established. Severely immunodeficient mice were able to be engrafted with ATL cell lines and have been used in preclinical studies of candidate molecules for the treatment of ATL. HTLV-1-infected humanized mice with an established human immune system are a suitable model to characterize cells in the early stages of HTLV-1 infection. This review outlines the characteristics of mouse models of HTLV-1 infection/ATL and describes progress made in elucidating the pathogenesis of ATL and developing related therapies using these mice.

BACKGROUND: In HTLV-1-associated malignant disease, adult T-cell leukaemia/lymphoma (ATLL), the interaction of virus and host was evaluated at the chemokines gene expression level. Also, IL-1β and Caspase-1 expressions were evaluated to investigate the importance of pyroptosis in disease development and progression.
RESULTS: The expression of host CCR6 and CXCR-3 and the HTLV-1 proviral load (PVL), Tax, and HBZ were assessed in 17 HTLV-1 asymptomatic carriers (ACs) and 12 ATLL patients using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR), TaqMan method. Moreover, RT-qPCR, SYBR Green assay were performed to measure Caspase-1 and IL-1β expression. HTLV-1-Tax did not express in 91.5% of the ATLLs, while HBZ was expressed in all ATLLs. The expression of CXCR3 dramatically decreased in ATLLs compared to ACs (p = 0.001). The expression of CCR6 was lower in ATLLs than ACs (p = 0.04). The mean of PVL in ATLL patients was statistically higher than ACs (p = 0.001). Furthermore, the expression of the IL-1β between ATLLs and ACs was not statistically significant (p = 0.4). In contrast, there was a meaningful difference between Caspase-1 in ATLLs and ACs (p = 0.02).
CONCLUSIONS: The present study indicated that in the first stage of ATLL malignancy toward acute lymphomatous, CXCR3 and its progression phase may target the pyroptosis process. Mainly, HBZ expression could be a novel therapeutic target.

Infection with human T-cell leukemia virus type 1 (HTLV-1) can produce a spectrum of pathological effects ranging from inflammatory disorders to leukemia. In vivo, HTLV-1 predominantly infects CD4+ T-cells. Infectious spread within this population involves the transfer of HTLV-1 virus particles from infected cells to target cells only upon cell-to-cell contact. The viral protein, HBZ, was found to enhance HTLV-1 infection through transcriptional activation of ICAM1 and MYOF, two genes that facilitate viral infection. In this study, we found that HBZ upregulates the transcription of COL4A1, GEM, and NRP1. COL4A1 and GEM are genes involved in viral infection, while NRP1, which encodes neuropilin 1 (Nrp1), serves as an HTLV-1 receptor on target cells but has no reported function on HTLV-1-infected cells. With a focus on Nrp1, cumulative results from chromatin immunoprecipitation assays and analyses of HBZ mutants support a model in which HBZ upregulates NRP1 transcription by augmenting recruitment of Jun proteins to an enhancer downstream of the gene. Results from in vitro infection assays demonstrate that Nrp1 expressed on HTLV-1-infected cells inhibits viral infection. Nrp1 was found to be incorporated into HTLV-1 virions, and deletion of its ectodomain removed the inhibitory effect. These results suggest that inhibition of HTLV-1 infection by Nrp1 is caused by the ectodomain of Nrp1 extended from virus particles, which may inhibit the binding of virus particles to target cells. While HBZ has been found to enhance HTLV-1 infection using cell-based models, there may be certain circumstances in which activation of Nrp1 expression negatively impacts viral infection, which is discussed.