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International Journal of Infectious... Aug 2024Infective dermatitis associated with human T-cell lymphotropic virus type-1 (HTLV-1) (IDH) is a severe form of chronically infected eczema occurring in early childhood,... (Review)
Review
Infective dermatitis associated with human T-cell lymphotropic virus type-1 (HTLV-1) (IDH) is a severe form of chronically infected eczema occurring in early childhood, although very rarely cases have been reported in adults. Most of the cases are from Jamaica and Brazil and occur in individuals with low socioeconomic status. IDH is always associated with refractory Staphylococcus aureus or beta-hemolytic Streptococcus infection of the skin and nasal vestibules. Patients with IDH may develop other even more severe HTLV-1-associated diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) of early or late appearance and adult T-cell leukemia/lymphoma. In the context of the Brazilian experience, it has been observed that 54% of IDH patients exhibit the juvenile form of HAM/TSP while the estimated incidence of adult HAM/TSP is 3%. As there are no curative treatments for HTLV-1 infection (or vaccines) or most of its associated diseases, prevention of infection is fundamental, mainly by vertical transmission, as it is responsible for the development of IDH, infantojuvenile HAM/TSP, and ATL. Public measures to reduce this transmission must be implemented urgently. Furthermore, it is recommended, mainly in HTLV-1 endemic areas, to search for HTLV-1 infection in all patients with infected eczema, even in adults.
Topics: Humans; HTLV-I Infections; Human T-lymphotropic virus 1; Brazil; Paraparesis, Tropical Spastic; Adult; Dermatitis
PubMed: 38697604
DOI: 10.1016/j.ijid.2024.107058 -
Frontiers in Immunology 2024Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma. The HTLV-1 Tax constitutively activates nuclear factor-κB...
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma. The HTLV-1 Tax constitutively activates nuclear factor-κB (NF-κB) to promote the survival and transformation of HTLV-1-infected T cells. Despite extensive study of Tax, how Tax interacts with host factors to regulate NF-κB activation and HTLV-1-driven cell proliferation is not entirely clear. Here, we showed that overexpression of Poly (rC)-binding protein 1 (PCBP1) promoted Tax-mediated IκB kinase (IKK)-NF-κB signaling activation, whereas knockdown of PCBP1 attenuated Tax-dependent IKK-NF-κB activation. However, Tax activation of HTLV-1 long terminal repeat was unaffected by PCBP1. Furthermore, depletion of PCBP1 led to apoptosis and reduced proliferation of HTLV-1-transformed cells. Mechanistically, PCBP1 interacted and co-localized with Tax in the cytoplasm, and PCBP1 KH3 domain was indispensable for the interaction between PCBP1 and Tax. Moreover, PCBP1 facilitated the assembly of Tax/IKK complex. Collectively, our results demonstrated that PCBP1 may exert an essential effect in Tax/IKK complex combination and subsequent NF-κB activation, which provides a novel insight into the pathogenetic mechanisms of HTLV-1.
Topics: Humans; Gene Products, tax; NF-kappa B; Human T-lymphotropic virus 1; RNA-Binding Proteins; DNA-Binding Proteins; Heterogeneous-Nuclear Ribonucleoproteins; Signal Transduction; HEK293 Cells; Protein Binding; Cell Proliferation; HTLV-I Infections; Apoptosis; I-kappa B Kinase; Host-Pathogen Interactions
PubMed: 38690287
DOI: 10.3389/fimmu.2024.1375168 -
The Journal of Veterinary Medical... Jun 2024The present study analyzed B-cell clonality and bovine leukemia virus (BLV) provirus integration sites in cattle with enzootic bovine leukosis (EBL) having BLV proviral...
The present study analyzed B-cell clonality and bovine leukemia virus (BLV) provirus integration sites in cattle with enzootic bovine leukosis (EBL) having BLV proviral copy numbers less or greater than the number of bovine nucleated cells. EBL cattle with BLV copy numbers less than the number of bovine nucleated cells showed monoclonal and biclonal proliferation of B-cells with one BLV provirus integration site. On the other hand, EBL cattle with BLV copy numbers greater than the number of bovine nucleated cells showed monoclonal proliferation of B-cells with two BLV provirus integration sites. These results suggest that superinfection of BLV can occur in EBL cattle.
Topics: Animals; Leukemia Virus, Bovine; Enzootic Bovine Leukosis; Cattle; Proviruses; DNA, Viral; B-Lymphocytes; Virus Integration; Cell Proliferation
PubMed: 38631888
DOI: 10.1292/jvms.24-0037 -
International Journal of Biological... May 2024Infection with bovine leukemia virus (BLV) leads to enzootic bovine leukosis, the most prevalent neoplastic disease in cattle. Due to the lack of commercially available...
Infection with bovine leukemia virus (BLV) leads to enzootic bovine leukosis, the most prevalent neoplastic disease in cattle. Due to the lack of commercially available vaccines, reliable eradication of the disease can be achieved through the testing and elimination of BLV antibody-positive animals. In this study, we developed a novel competitive ELISA (cELISA) to detect antibodies against BLV capsid protein p24. Recombinant p24 protein expressed by Escherichia coli, in combination with the monoclonal antibody 2G11 exhibiting exceptional performance, was used for the establishment of the cELISA. Receiver-operating characteristic curve analysis showed that the sensitivity and specificity of the assay were 98.85 % and 98.13 %, respectively. Furthermore, the established cELISA was specific for detecting BLV-specific antibodies, without cross-reactivity to antisera for six other bovine viruses. Significantly, experimental infection of cattle and sheep with BLV revealed that the cELISA accurately monitors seroconversion. In a performance evaluation, the established cELISA displayed a high agreement with Western blotting and the commercial BLV gp51 cELISA kit in the detection of 242 clinical samples, respectively. In conclusion, the novel p24 cELISA exhibited the potential to be a reliable and efficient diagnostic tool for BLV serological detection with a broad application prospect.
Topics: Leukemia Virus, Bovine; Animals; Enzyme-Linked Immunosorbent Assay; Cattle; Antibodies, Viral; Antibodies, Monoclonal; Enzootic Bovine Leukosis; Capsid Proteins; Sensitivity and Specificity; Recombinant Proteins; ROC Curve
PubMed: 38621561
DOI: 10.1016/j.ijbiomac.2024.131446 -
International Journal of Molecular... Mar 2024Human T-cell leukemia virus type 1 (HTLV-1), a virus that affects 5-10 million people globally, causes several diseases, including adult T-cell leukemia-lymphoma and...
Human T-cell leukemia virus type 1 (HTLV-1), a virus that affects 5-10 million people globally, causes several diseases, including adult T-cell leukemia-lymphoma and HTLV-1-associated uveitis (HU). HU is prevalent in Japan and often leads to secondary glaucoma, which is a serious complication. We investigated the efficacy of ripasudil, a Rho-associated coiled coil-forming protein kinase inhibitor, in alleviating changes in human trabecular meshwork cells (hTM cells) infected with HTLV-1. HTLV-1-infected hTM cells were modeled in vitro using MT-2 cells, followed by treatment with varying concentrations of ripasudil. We assessed changes in cell morphology, viability, and inflammatory cytokine levels, as well as NF-κB activation. The results showed that ripasudil treatment changed the cell morphology, reduced the distribution of F-actin and fibronectin, and decreased the levels of certain inflammatory cytokines, such as interleukin (IL)-6, IL-8, and IL-12. However, ripasudil did not significantly affect NF-κB activation or overall cell viability. These findings suggest that ripasudil has the potential to treat secondary glaucoma in patients with HU by modulating cytoskeletal organization and alleviating inflammation in HTLV-1-infected hTM cells. This study lays the foundation for further clinical studies exploring the effectiveness of ripasudil for the treatment of secondary glaucoma associated with HU.
Topics: Adult; Humans; Human T-lymphotropic virus 1; NF-kappa B; Glaucoma; Uveitis; Cytokines; Interleukin-6; rho-Associated Kinases; Isoquinolines; Sulfonamides
PubMed: 38542203
DOI: 10.3390/ijms25063229 -
Journal of Veterinary Research Mar 2024Bovine leukaemia virus (BLV) is a Deltaretrovirus responsible for enzootic bovine leukosis, the most common neoplastic disease of cattle. It deregulates the immune...
INTRODUCTION
Bovine leukaemia virus (BLV) is a Deltaretrovirus responsible for enzootic bovine leukosis, the most common neoplastic disease of cattle. It deregulates the immune system, favouring secondary infections and changes in the blood and lymphatic tissues. Blood homeostasis depends on functional haematopoietic stem cells (HSCs). Bone marrow is populated by these cells, which express CD34 and CD35 surface antigens and produce and release cytokines involved in the maintenance of haematopoiesis. The aim of the study was determination of the profile of cytokine production by CD34 stem cells of cattle naturally infected with BLV.
MATERIAL AND METHODS
The HSCs were generated from the blood and lymphoid organs of cows infected with BLV and healthy control cows with immunomagnetic separation and anti-CD34 monoclonal antibodies. Isolated CD34 cells were cultivated for two weeks with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. The levels of IL-6, IL-10, IL-12p40, IL-12p70, interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) were determined in culture fluid by flow cytometry.
RESULTS
The expression of IL-6, IL-12p70 and TNF-α in blood HSCs was higher in BLV cows than in the control animals. In bone marrow HSCs of infected cows, IL-12, TNF-α and IFN-γ were more concentrated, but in these cows' spleen HSCs only expression of IL-10 was elevated. In HSCs isolated from the lymph nodes of leukaemic cows, only TNF-α secretion was lower than in control cows, the other cytokines being more potently secreted.
CONCLUSION
Infection with BLV caused statistically significant differences in cytokine expression by HSC CD34 cells.
PubMed: 38525233
DOI: 10.2478/jvetres-2024-0012 -
International Journal of Infectious... Jun 2024Human T-lymphotropic viruses (HTLV)-1 infection is endemic in many countries of Central and South America and Caribbean (CSA&C). Neither screening nor surveillance... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Human T-lymphotropic viruses (HTLV)-1 infection is endemic in many countries of Central and South America and Caribbean (CSA&C). Neither screening nor surveillance programs exist for HTLV-1/2 infection among pregnant women in this region. Neither in Western nations with large migrant flows from HTLV-1/2 endemic regions.
METHODS
Systematic review and meta-analysis of the prevalence of HTLV-1/2 infection among CSA&C pregnant women. We included studies searching EMBASE, PubMed/MEDLINE, Scopus, and Web of Science from inception to February 15, 2023. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines.
RESULTS
We identified a total of 620 studies. Only 41 were finally included in the meta-analysis. Most studies (61.0%) were from Brazil and Peru (14.6%). The total number of participants was 343,707. The pooled prevalence of HTLV-1/2 infection among CSA&C pregnant women was 1.30% (95% CI: 0.96-1.69) using anti-HTLV-1/2 antibody screening tests. There was a high heterogeneity (I = 98.6%). Confirmatory tests gave an HTLV-1 infection rate of 1.02% (95% CI: 0.75-1.33).
CONCLUSIONS
The prevalence of HTLV-1/2 infection among CSA&C pregnant women is 1.3%, most cases being HTLV-1. This rate is greater than for other microbial agents regularly checked as part of antenatal screening (such as HIV, hepatitis B, or syphilis). Thus, HTLV-1/2 antenatal testing should be mandatory among CSA&C pregnant women everywhere.
Topics: Humans; Pregnancy; Female; HTLV-I Infections; HTLV-II Infections; Prevalence; Caribbean Region; South America; Human T-lymphotropic virus 1; Pregnancy Complications, Infectious; Human T-lymphotropic virus 2; Central America
PubMed: 38522611
DOI: 10.1016/j.ijid.2024.107018 -
Proceedings of the National Academy of... Mar 2024Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts,...
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 () 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 and . 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.
Topics: Humans; Cell Line; Virulence; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; Proviruses; Transforming Growth Factor beta; Basic-Leucine Zipper Transcription Factors; APOBEC-3G Deaminase
PubMed: 38502701
DOI: 10.1073/pnas.2309925121 -
Chemical & Pharmaceutical Bulletin 2024The inhibition mode of a retro-inverso (RI) inhibitor containing a hydroxyethylamine dipeptide isostere against the human T-cell leukemia virus type-1 (HTLV-1) protease...
The inhibition mode of a retro-inverso (RI) inhibitor containing a hydroxyethylamine dipeptide isostere against the human T-cell leukemia virus type-1 (HTLV-1) protease was examined. Enzymatic evaluation of the RI-modified inhibitor containing a D-allo-Ile residue revealed that HTLV-1 was competitively inhibited. IC values of the RI-modified inhibitor and pepstatin A, a standard inhibitor of aspartic proteases, were nearly equivalent.
Topics: Humans; Amino Acid Sequence; Aspartic Acid Endopeptidases; Human T-lymphotropic virus 1; Dipeptides; Protease Inhibitors
PubMed: 38479891
DOI: 10.1248/cpb.c23-00879 -
Journal of Neurology Jun 2024Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter,... (Randomized Controlled Trial)
Randomized Controlled Trial
Multicenter, randomized, double-blind, placebo-controlled phase 3 study of mogamulizumab with open-label extension study in a minimum number of patients with human T-cell leukemia virus type-1-associated myelopathy.
Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (- 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60-80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).
Topics: Humans; Double-Blind Method; Antibodies, Monoclonal, Humanized; Male; Middle Aged; Female; Paraparesis, Tropical Spastic; Adult; Aged; Neopterin; Human T-lymphotropic virus 1; Chemokine CXCL10; Viral Load; Treatment Outcome
PubMed: 38430272
DOI: 10.1007/s00415-024-12239-x