scholarly journals Interactome and structural basis for targeting the human T-cell leukemia virus Tax oncoprotein

2021 ◽  
Author(s):  
Sibusiso B. Maseko ◽  
Inge Van Molle ◽  
Karim Blibek ◽  
Christoph Gorgulla ◽  
Julien Olivet ◽  
...  
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
Pdz Domain ◽  
Structural Basis ◽  
List Type ◽  
T Cell Leukemia ◽  
Pdz Domains ◽  
Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

SUMMARYHuman T-cell leukemia virus type-1 (HTLV-1) is the first pathogenic retrovirus discovered in human. Although HTLV-1-induced diseases are well characterized and linked to the encoded Tax-1 protein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we report a comprehensive interaction map between Tax-1 and human PDZ domain-containing proteins (hPDZome), and we show that Tax-1 interacts with one-third of them. This includes proteins involved in cell cycle, cell-cell junction and cytoskeleton organization, as well as in membrane complexes assembly. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the structural basis of the interaction between the C-terminal PDZ binding motif (PBM) of Tax-1, and the PDZ domains of DLG1 and syntenin-1. Finally, we have used molecular modeling and mammalian cell-based assays to demonstrate that Tax-1/PDZ-domain interactions are amenable to small-molecule inhibition. Thus, our work provides a framework for the design of targeted therapies for HTLV-1-induced diseases.Highlightscomprehensive interactome map of HTLV-1 Tax / human PDZ proteinsbasis of Tax-1 PBM binding to human DLG1 and syntenin-1 PDZ domains”.significance of inhibiting Tax-1 functionsof the Tax-1 / PDZ interfaceGraphical abstract

scholarly journals Structural basis of host protein hijacking in human T-cell leukemia virus integration

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Veer Bhatt ◽  
Ke Shi ◽  
Daniel J. Salamango ◽  
Nicholas H. Moeller ◽  
Krishan K. Pandey ◽  
...  
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
Host Protein ◽  
Structural Basis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Virus Integration

scholarly journals Biochemical Characterization, Specificity and Inhibition Studies of HTLV-1, HTLV-2, and HTLV-3 Proteases

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 127
Author(s):  
Norbert Kassay ◽  
János András Mótyán ◽  
Krisztina Matúz ◽  
Mária Golda ◽  
József Tőzsér
Keyword(s):  
T Cell ◽  
Biochemical Characterization ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

The human T-lymphotropic viruses (HTLVs) are causative agents of severe diseases including adult T-cell leukemia. Similar to human immunodeficiency viruses (HIVs), the viral protease (PR) plays a crucial role in the viral life-cycle via the processing of the viral polyproteins. Thus, it is a potential target of anti-retroviral therapies. In this study, we performed in vitro comparative analysis of human T-cell leukemia virus type 1, 2, and 3 (HTLV-1, -2, and -3) proteases. Amino acid preferences of S4 to S1′ subsites were studied by using a series of synthetic oligopeptide substrates representing the natural and modified cleavage site sequences of the proteases. Biochemical characteristics of the different PRs were also determined, including catalytic efficiencies and dependence of activity on pH, temperature, and ionic strength. We investigated the effects of different HIV-1 PR inhibitors (atazanavir, darunavir, DMP-323, indinavir, ritonavir, and saquinavir) on enzyme activities, and inhibitory potentials of IB-268 and IB-269 inhibitors that were previously designed against HTLV-1 PR. Comparative biochemical analysis of HTLV-1, -2, and -3 PRs may help understand the characteristic similarities and differences between these enzymes in order to estimate the potential of the appearance of drug-resistance against specific HTLV-1 PR inhibitors.

scholarly journals Transformed T lymphocytes infected by a novel isolate of human T cell leukemia virus type II

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1336-1342 ◽  
Author(s):  
TL Chorba ◽  
R Brynes ◽  
VS Kalyanaraman ◽  
M Telfer ◽  
R Ramsey ◽  
...  
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
Type Ii ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
T Helper ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
Viral Particles ◽  
T Cell Leukemia Virus

Abstract Human T cell leukemia virus type II (HTLV-II) has been isolated from a patient (Mo) with features of leukemic reticuloendotheliosis (LRE) and from a patient with acquired immunodeficiency syndrome (AIDS). We have obtained another isolate of HTLV-II from a patient (CM) with severe hemophilia A, pancytopenia, and a 14-year history of staphylococcal and candidal infections but no evidence of T cell leukemia/lymphoma, AIDS, or LRE. Fresh mononuclear cells and cultured lymphocytes from CM express retroviral antigens indistinguishable by molecular criteria from HTLV-IIMo. Leukocyte cultures from CM yield hyperdiploid (48,XY, +2, +19) continuous lymphoid lines; human fetal cord blood lymphocytes (CBL) are transformed by cocultivation with these CM cell cultures but retain normal cytogenetic constitution. Electron microscopic examination of the CM cultures and transformed CBL reveals budding of extracellular viral particles, intracellular tubuloreticular structures, and viral particles contained within intracellular vesicles. CM cell cultures and the transformed CBL do not require exogenous interleukin 2, have T cell cytochemical features and mature T helper phenotypes, and exhibit minimal T helper and profound T suppressor activity on pokeweed mitogen-stimulated differentiation of normal B cells. These characteristics, which are similar to those observed with the first HTLV-II isolate, may represent properties of all HTLV-II-infected T cells.

scholarly journals Smoking is a risk factor for development of adult T-cell leukemia/lymphoma in Japanese human T-cell leukemia virus type-1 carriers

2016 ◽  
Vol 27 (9) ◽  
pp. 1059-1066 ◽  
Author(s):  
Hisayoshi Kondo ◽  
Midori Soda ◽  
Norie Sawada ◽  
Manami Inoue ◽  
Yoshitaka Imaizumi ◽  
...  
Keyword(s):  
Risk Factor ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

scholarly journals Proviral Features of Human T Cell Leukemia Virus Type 1 in Carriers with Indeterminate Western Blot Analysis Results

2017 ◽  
Vol 55 (9) ◽  
pp. 2838-2849 ◽  
Author(s):  
Madoka Kuramitsu ◽  
Tsuyoshi Sekizuka ◽  
Tadanori Yamochi ◽  
Sanaz Firouzi ◽  
Tomoo Sato ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Proviral Load ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACTWestern blotting (WB) for human T cell leukemia virus type 1 (HTLV-1) is performed to confirm anti-HTLV-1 antibodies detected at the initial screening of blood donors and in pregnant women. However, the frequent occurrence of indeterminate results is a problem with this test. We therefore assessed the cause of indeterminate WB results by analyzing HTLV-1 provirus genomic sequences. A quantitative PCR assay measuring HTLV-1 provirus in WB-indeterminate samples revealed that the median proviral load was approximately 100-fold lower than that of WB-positive samples (0.01 versus 0.71 copy/100 cells). Phylogenic analysis of the complete HTLV-1 genomes of WB-indeterminate samples did not identify any specific phylogenetic groups. When we analyzed the nucleotide changes in 19 HTLV-1 isolates from WB-indeterminate samples, we identified 135 single nucleotide substitutions, composed of four types, G to A (29%), C to T (19%), T to C (19%), and A to G (16%). In the most frequent G-to-A substitution, 64% occurred at GG dinucleotides, indicating that APOBEC3G is responsible for mutagenesis in WB-indeterminate samples. Moreover, interestingly, five WB-indeterminate isolates had nonsense mutations in Pol and/or Tax, Env, p12, and p30. These findings suggest that WB-indeterminate carriers have low production of viral antigens because of a combination of a low proviral load and mutations in the provirus, which may interfere with host recognition of HTLV-1 antigens.

Long terminal repeat structure of an american isolate of type I human T-cell leukemia virus

Virology ◽  
1984 ◽  
Vol 139 (2) ◽  
pp. 340-345 ◽  
Author(s):  
S.F. Josephs ◽  
F. Wong-Staal ◽  
V. Manzari ◽  
R.C. Gallo ◽  
J.G. Sodroski ◽  
...  
Keyword(s):  
T Cell ◽  
Long Terminal Repeat ◽  
Leukemia Virus ◽  
Terminal Repeat ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Repeat Structure ◽  
Human T Cell ◽  
T Cell Leukemia Virus
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