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Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 152
Svetlana Kalinichenko ◽  
Dmitriy Komkov ◽  
Dmitriy Mazurov

So far, only two retroviruses, human immunodeficiency virus (HIV) (type 1 and 2) and human T-cell lymphotropic virus type 1 (HTLV-1), have been recognized as pathogenic for humans. Both viruses mainly infect CD4+ T lymphocytes. HIV replication induces the apoptosis of CD4 lymphocytes, leading to the development of acquired immunodeficiency syndrome (AIDS). After a long clinical latency period, HTLV-1 can transform lymphocytes, with subsequent uncontrolled proliferation and the manifestation of a disease called adult T-cell leukemia (ATLL). Certain infected patients develop neurological autoimmune disorder called HTLV-1-associated myelopathy, also known as tropical spastic paraparesis (HAM/TSP). Both viruses are transmitted between individuals via blood transfusion, tissue/organ transplantation, breastfeeding, and sexual intercourse. Within the host, these viruses can spread utilizing either cell-free or cell-to-cell modes of transmission. In this review, we discuss the mechanisms and importance of each mode of transmission for the biology of HIV-1 and HTLV-1.

Anusara Daenthanasanmak ◽  
Richard N Bamford ◽  
Makoto Yoshioka ◽  
Shyh-Ming Yang ◽  
Philip John Homan ◽  

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell lymphoproliferative malignancy, caused by human T-cell leukemia virus type 1 (HTLV-1). ATL is an orphan disease with no curative drug treatment regimens, urgently needing new combination therapy. HTLV-1-infected cells rely on viral proteins, Tax and HBZ (HTLV-1-b-ZIP factor), to activate the transcription of various host genes that are critical for promoting leukemic transformation. Inhibition of bromodomain and extra-terminal motif (BET) protein was previously shown to collapse the transcriptional network directed by BATF3 super-enhancer and thereby induced ATL cell apoptosis. In the current work, by using xenograft, ex vivo, and in vitro models, we demonstrated that I-BET762 (BETi) synergized with copanlisib (PI3Ki) and bardoxolone methyl (NF-κBi) to dramatically decrease the growth of ATL cells. Mechanistically, the triple combination exhibited synergistic activity by down-regulating the expression of c-MYC while up-regulating the level of the glucocorticoid-induced leucine zipper (GILZ). The triple combination also enhanced apoptosis induction by elevating the expression of active caspase-3 and cleaved PARP. Importantly, the triple combination prolonged the survival of ATL-bearing xenograft mice and inhibited the proliferation of ATL cells from PBMCs of both acute and smoldering/chronic ATL patients. Therefore, our data provide the rationale for a clinical trial exploring the multi-agent combination of BET, PI3K/AKT, and NF-κB inhibitors for ATL patients, and expands the potential treatments for this recalcitrant malignancy.

2022 ◽  
Vol 16 (1) ◽  
pp. e0009772
José Abraão Carneiro Neto ◽  
Cássius José Vitor de Oliveira ◽  
Sheila Nunes Ferraz ◽  
Mariele Guerra ◽  
Lívia Alves Oliveira ◽  

Background While bladder dysfunction is observed in the majority of patients with human T cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM), it is also observed in patients who do not fulfill all diagnostic criteria for HAM. These patients are classified as having possible or probable HAM/TSP. However, it remains unclear whether the severity and progression of bladder dysfunction occurs similarly between these two groups. Objective Compare the severity and evolution of bladder dysfunction in HTLV-1-infected patients with possible and definite HAM/TSP. Methods The present prospective cohort study followed 90 HTLV-1 patients with possible HAM/TSP and 84 with definite HAM/TSP between April 2011 and February 2019. Bladder dysfunction was evaluated by bladder diary, overactive bladder symptoms scores (OABSS) and urodynamic studies. Bladder dysfunction progression was defined as the need for clean self-intermittent catheterization (CIC). Results At baseline, nocturia, urgency and OABSS scores were worse in definite compared to possible HAM/TSP patients. The main urodynamic finding was detrusor overactivity, present in 77.8% of the patients with definite HAM/TSP versus 58.7% of those with possible HAM/TSP (P = 0.05). Upon study conclusion, the cumulative frequency of patients requiring CIC increased in both groups, from 2 to 6 in possible HAM/TSP and from 28 to 44 in definite HAM/TSP patients. The estimated time to need for CIC was 6.7 years (95%CI 6.5–7.0) in the possible HAM/TSP group compared to 5.5 years (95%CI 4.8–6.1) in the definite HAM/TSP group. Conclusions Although both groups showed similarities in bladder dysfunction and tended to progress to requiring CIC over time, patients with possible HAM/TSP presented less severe manifestations at baseline and progressed more slowly than those with definite HAM/TSP.

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 138
Victoria Maksimova ◽  
Amanda R. Panfil

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal CD4+ T-cell malignancy, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic neurological disease. Disease progression in infected individuals is the result of HTLV-1-driven clonal expansion of CD4+ T-cells and is generally associated with the activities of the viral oncoproteins Tax and Hbz. A closely related virus, HTLV-2, exhibits similar genomic features and the capacity to transform T-cells, but is non-pathogenic. In vitro, HTLV-1 primarily immortalizes or transforms CD4+ T-cells, while HTLV-2 displays a transformation tropism for CD8+ T-cells. This distinct tropism is recapitulated in infected people. Through comparative studies, the genetic determinant for this divergent tropism of HTLV-1/2 has been mapped to the viral envelope (Env). In this review, we explore the emerging roles for Env beyond initial viral entry and examine current perspectives on its contributions to HTLV-1-mediated disease development.

2021 ◽  
Vol 10 (1) ◽  
pp. 84
Lee Ratner

Viral and cellular gene expression are regulated by epigenetic alterations, including DNA methylation, histone modifications, nucleosome positioning, and chromatin looping. Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus associated with inflammatory disorders and T-cell lymphoproliferative malignancy. The transforming activity of HTLV-1 is driven by the viral oncoprotein Tax, which acts as a transcriptional activator of the cAMP response element-binding protein (CREB) and nuclear factor kappa B (NFκB) pathways. The epigenetic effects of Tax and the induction of lymphoproliferative malignancy include alterations in DNA methylation and histone modifications. In addition, alterations in nucleosome positioning and DNA looping also occur in HTLV-1-induced malignant cells. A mechanistic definition of these effects will pave the way to new therapies for HTLV-1-associated disorders.

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 83
Marina Aparicio-Soto ◽  
Caterina Curato ◽  
Franziska Riedel ◽  
Hermann-Josef Thierse ◽  
Andreas Luch ◽  

Background: Chemical allergies are T cell-mediated diseases that often manifest in the skin as allergic contact dermatitis (ACD). To prevent ACD on a public health scale and avoid elicitation reactions at the individual patient level, predictive and diagnostic tests, respectively, are indispensable. Currently, there is no validated in vitro T cell assay available. The main bottlenecks concern the inefficient generation of T cell epitopes and the detection of rare antigen-specific T cells. Methods: Here, we systematically review original experimental research papers describing T cell activation to chemical skin sensitizers. We focus our search on studies published in the PubMed and Scopus databases on non-metallic allergens in the last 20 years. Results: We identified 37 papers, among them 32 (86%) describing antigen-specific human T cell activation to 31 different chemical allergens. The remaining studies measured the general effects of chemical allergens on T cell function (five studies, 14%). Most antigen-specific studies used peripheral blood mononuclear cells (PBMC) as antigen-presenting cells (APC, 75%) and interrogated the blood T cell pool (91%). Depending on the individual chemical properties, T cell epitopes were generated either by direct administration into the culture medium (72%), separate modification of autologous APC (29%) or by use of hapten-modified model proteins (13%). Read-outs were mainly based on proliferation (91%), often combined with cytokine secretion (53%). The analysis of T cell clones offers additional opportunities to elucidate the mechanisms of epitope formation and cross-reactivity (13%). The best researched allergen was p-phenylenediamine (PPD, 12 studies, 38%). For this and some other allergens, stronger immune responses were observed in some allergic patients (15/31 chemicals, 48%), illustrating the in vivo relevance of the identified T cells while detection limits remain challenging in many cases. Interpretation: Our results illustrate current hardships and possible solutions to monitoring T cell responses to individual chemical skin sensitizers. The provided data can guide the further development of T cell assays to unfold their full predictive and diagnostic potential, including cross-reactivity assessments.

2021 ◽  
Liu Huandi ◽  
Jiaxiang Sun ◽  
Shuaifeng Guo ◽  
Xuhong Cheng ◽  
Zhongxin Zhang ◽  

Abstract Background: Hydrogen sulfide(H 2 S)is a redox gasotransmitter. It has been shown that H 2 S has a key role in host antiviral defense by inhibiting interleukin (IL)-6 production and S-sulfhydrating Keap1 lead to Nrf2/ARE pathway activation. However, it is yet unclear whether H 2 S can play an antiviral role by regulating autophagy. Results: In this research, we found that exogenous H 2 S decreased the expression of HTLV-1 protein and HTLV-1 induced autophagosomes accumulation. Transmission electron microscope assays indicated that autophagosomes accumulation decreased after H 2 S administration. HTLV-1-transformed T-cell lines had a high level of CSE (H 2 S endogenous enzyme) which could be induced in Hela by HTLV-1 infection. Immunoblot demonstrated that overexpression of CSE inhibited HTLV-1 protein expression and autophagy. And we got the opposite after CSE knockdown. Meanwhile, H 2 S could not restrain the autophagy when ATG4B had a mutant at its site of 89. Conclusion: In a word, these results suggested that H 2 S modulated HTLV-1 protein expression via ATG4B. Meanwhile, our findings suggested a new mechanism by which H 2 S defended against virus infection.

2021 ◽  
Vol 22 (24) ◽  
pp. 13597
Stephan Kohrt ◽  
Sarah Strobel ◽  
Melanie Mann ◽  
Heinrich Sticht ◽  
Bernhard Fleckenstein ◽  

The human T-cell leukemia virus type 1 (HTLV-1)-encoded transactivator and oncoprotein Tax-1 is essential for HTLV-1 replication. We recently found that Tax-1 interacts with transcription elongation factor for RNA polymerase II 2, ELL2, which enhances Tax-1-mediated transactivation of the HTLV-1 promotor. Here, we characterize the Tax-1:ELL2 interaction and its impact on viral transactivation by confocal imaging, co-immunoprecipitation, and luciferase assays. We found that Tax-1 and ELL2 not only co-precipitate, but also co-localize in dot-like structures in the nucleus. Tax-1:ELL2 complex formation occurred independently of Tax-1 point mutations, which are crucial for post translational modifications (PTMs) of Tax-1, suggesting that these PTMs are irrelevant for Tax-1:ELL2 interaction. In contrast, Tax-1 deletion mutants lacking either N-terminal (aa 1–37) or C-terminal regions (aa 150–353) of Tax-1 were impaired in interacting with ELL2. Contrary to Tax-1, the related, non-oncogenic Tax-2B from HTLV-2B did not interact with ELL2. Finally, we found that ELL2-R1 (aa 1–353), which carries an RNA polymerase II binding domain, and ELL2-R3 (aa 515–640) are sufficient to interact with Tax-1; however, only ELL2-truncations expressing R1 could enhance Tax-1-mediated transactivation of the HTLV-1 promoter. Together, this study identifies domains in Tax-1 and ELL2 being required for Tax-1:ELL2 complex formation and for viral transactivation.

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