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BMC Infectious Diseases Jan 2024Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown. (Observational Study)
Observational Study
BACKGROUND
Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown.
METHODS
To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors.
RESULTS
We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers.
CONCLUSIONS
The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.
Topics: Humans; Aged; Human T-lymphotropic virus 1; COVID-19; COVID-19 Vaccines; Immunity, Humoral; Prospective Studies; HTLV-I Infections; Hypertension; Vaccination; Diabetes Mellitus; Dyslipidemias; Immunoglobulin G; Antibodies, Viral
PubMed: 38233756
DOI: 10.1186/s12879-024-09001-z -
Vox Sanguinis Mar 2024Serological HTLV-1/2 screening is mandatory for blood donor candidates in Brazil. Our objective was to analyse HTLV test results in blood donors submitted for screening...
BACKGROUND AND OBJECTIVES
Serological HTLV-1/2 screening is mandatory for blood donor candidates in Brazil. Our objective was to analyse HTLV test results in blood donors submitted for screening and confirmatory assays in a Brazilian blood bank.
MATERIALS AND METHODS
Retrospective analysis (2017-2022) results of chemiluminescence immunoassays and confirmatory tests for HTLV-1/2 in reactive donors were performed. During the analysed period, three sets of assays were used: (1) Architect rHTLV-I/II + HTLV Blot 2.4 (Western blot [WB]); (2) Alinity s HTLV I/II Reagent Kit + INNO-line immunoassay (LIA) HTLV I/II Score (LIA); (3) Alinity + WB.
RESULTS
The analysed period comprised a total of 1,557,333 donations. The mean percentage of HTLV reactive donors using the Architect assay was 0.14%. With the change to the Alinity assay, that percentage dropped 2.3-fold (0.06%). The reactivity rate in the confirmatory tests (1064 samples) ranged from 13.5% to 30.2%, whereas 58.3%-85.9% of samples were non-reactive. The highest rates of positive (30.2%) and indeterminate (11.5%) results were seen using LIA. Considering all analysed samples, those with signal/cut-off ratio (S/CO) >50 were positive in confirmatory tests (positive predictive value, PPV = 100%), whereas samples with S/CO ≤6 are very unlikely to be truly positive (PPV = 0).
CONCLUSION
The use of the Alinity assay reduced the frequency of false-positive results. Confirmatory tests are important to identify true HTLV infection in blood donors, because more than 58% of initially reactive individuals are confirmed as seronegative. Categorizing S/CO values is useful for assessing the likelihood of true HTLV-1/2 infection.
Topics: Humans; Blood Donors; Retrospective Studies; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; HTLV-I Infections; Blotting, Western; T-Lymphocytes
PubMed: 38223953
DOI: 10.1111/vox.13577 -
Virology Journal Jan 2024The human T-lymphotropic virus type 1 (HTLV-1) infects millions of people globally and is endemic to various resource-limited regions. Infections persist for life and...
The human T-lymphotropic virus type 1 (HTLV-1) infects millions of people globally and is endemic to various resource-limited regions. Infections persist for life and are associated with increased susceptibility to opportunistic infections and severe diseases including adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. No HTLV-1-specific anti-retrovirals have been developed and it is unclear whether existing anti-retrovirals developed for treatment of human immunodeficiency virus (HIV) have efficacy against HTLV-1. To understand the structural basis for therapeutic binding, homology modelling and machine learning were used to develop a structural model of the HTLV-1 reverse transcriptase. With this, molecular docking experiments using a panel of FDA-approved inhibitors of viral reverse transcriptases to assess their capacity for binding, and in turn, inhibition. Importantly, nucleoside/nucleotide reverse transcriptase inhibitor but not non-nucleoside reverse transcriptase inhibitors were predicted to bind the HTLV-1 reverse transcriptase, with similar affinity to HIV-1 reverse transcriptase. By strengthening the rationale for clinical testing of therapies such as tenofovir alafenamide, zidovudine, lamivudine, and azvudine for treatment of HTLV-1, this study has demonstrated the power of in silico structural biology approaches in drug design and therapeutic testing.
Topics: Adult; Humans; Human T-lymphotropic virus 1; Nucleotides; Reverse Transcriptase Inhibitors; Molecular Docking Simulation; Paraparesis, Tropical Spastic
PubMed: 38200531
DOI: 10.1186/s12985-024-02288-z -
Journal of Virology Feb 2024Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma, a severe and fatal CD4+ T-cell malignancy. Additionally,...
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma, a severe and fatal CD4+ T-cell malignancy. Additionally, HTLV-1 can lead to a chronic progressive neurodegenerative disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis. Unfortunately, the prognosis for HTLV-1-related diseases is generally poor, and effective treatment options are limited. In this study, we designed and synthesized a codon optimized HTLV-1 envelope (Env) mRNA encapsulated in a lipid nanoparticle (LNP) and evaluated its efficacy as a vaccine candidate in an established rabbit model of HTLV-1 infection and persistence. Immunization regimens included a prime/boost protocol using Env mRNA-LNP or control green fluorescent protein (GFP) mRNA-LNP. After immunization, rabbits were challenged by intravenous injection with irradiated HTLV-1 producing cells. Three rabbits were partially protected and three rabbits were completely protected against HTLV-1 challenge. These rabbits were then rechallenged 15 weeks later, and two rabbits maintained sterilizing immunity. In Env mRNA-LNP immunized rabbits, proviral load and viral gene expression were significantly lower. After viral challenge in the Env mRNA-LNP vaccinated rabbits, an increase in both CD4+/IFN-γ+ and CD8+/IFN-γ+ T-cells was detected when stimulating with overlapping Env peptides. Env mRNA-LNP elicited a detectable anti-Env antibody response after prime/boost vaccination in all animals and significantly higher levels of neutralizing antibody activity. Neutralizing antibody activity was correlated with a reduction in proviral load. These findings hold promise for the development of preventive strategies and therapeutic interventions against HTLV-1 infection and its associated diseases.IMPORTANCEmRNA vaccine technology has proven to be a viable approach for effectively triggering immune responses that protect against or limit viral infections and disease. In our study, we synthesized a codon optimized human T-cell leukemia virus type 1 (HTLV-1) envelope (Env) mRNA that can be delivered in a lipid nanoparticle (LNP) vaccine approach. The HTLV-1 Env mRNA-LNP produced protective immune responses against viral challenge in a preclinical rabbit model. HTLV-1 is primarily transmitted through direct cell-to-cell contact, and the protection offered by mRNA vaccines in our rabbit model could have significant implications for optimizing the development of other viral vaccine candidates. This is particularly important in addressing the challenge of enhancing protection against infections that rely on cell-to-cell transmission.
Topics: Animals; Humans; Rabbits; Antibodies, Neutralizing; Antibody Formation; Codon; Human T-lymphotropic virus 1; Leukemia, T-Cell; mRNA Vaccines; Neurodegenerative Diseases; RNA, Messenger; Viral Vaccines
PubMed: 38193692
DOI: 10.1128/jvi.01623-23 -
JCI Insight Jan 2024Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection...
Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection to adult T cell leukemia and HTLV-1-associated myelopathy (HAM), an inflammatory disease of the CNS. The mechanisms by which HTLV-1 induces HAM are poorly understood. By directly examining the ex vivo phenotype and function of T cells from asymptomatic carriers and patients with HAM, we show that patients with HAM have a higher frequency of CD4+CD8+ double-positive (DP) T cells, which are infected with HTLV-1 at higher rates than CD4+ T cells. Displaying both helper and cytotoxic phenotypes, these DP T cells are highly proinflammatory and contain high frequencies of HTLV-1-specific cells. Mechanistically, we demonstrate that DP T cells arise by direct HTLV-1 infection of CD4+ and CD8+ T cells. High levels of CD49d and CXCR3 expression suggest that DP T cells possess the ability to migrate to the CNS, and when cocultured with astrocytes, DP T cells induce proinflammatory astrocytes that express high levels of CXCL10, IFN-γ, and IL-6. These results demonstrate the potential of DP T cells to directly contribute to CNS pathology.
Topics: Humans; Astrocytes; Bone Marrow Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Human T-lymphotropic virus 1; Paraparesis, Tropical Spastic
PubMed: 38193535
DOI: 10.1172/jci.insight.173738 -
Blood Advances Mar 2024Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine...
Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrantly in HTLV-1-infected T cells but not in normal T cells. T-cell activation via T-cell receptor (TCR) signaling induced expression of UCK2 in normal T cells. Somatic alterations and epigenetic modifications in ATL cells activate TCR signaling. Therefore, we believe that expression of UCK2 in HTLV-1-infected cells is induced by dysregulated TCR signaling. Recently, we established azacitidine-resistant (AZA-R) cells showing absent expression of UCK2. AZA-R cells proliferated normally in vitro, whereas UCK2 knockdown inhibited ATL cell growth. Although uridine and cytidine accumulated in AZA-R cells, possibly because of dysfunction of pyrimidine salvage biosynthesis induced by loss of UCK2 expression, the amount of UTP and CTP was almost the same as in parental cells. Furthermore, AZA-R cells were more susceptible to an inhibitor of dihydroorotic acid dehydrogenase, which performs the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, and more resistant to dipyridamole, an inhibitor of pyrimidine salvage biosynthesis, suggesting that AZA-R cells adapt to UCK2 loss by increasing de novo pyrimidine nucleotide biosynthesis. Taken together, the data suggest that fine-tuning pyrimidine biosynthesis supports vigorous cell proliferation of both normal T cells and ATL cells.
Topics: Adult; Humans; Pyrimidines; Uridine; Cell Proliferation; Cytidine; Human T-lymphotropic virus 1; Pyrimidine Nucleotides; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 38190613
DOI: 10.1182/bloodadvances.2023011131 -
Veterinary Immunology and... Feb 2024Bovines infected by bovine leukemia virus (BLV) are characterized by presenting low proviral load (LPL) or high proviral load (HPL). It is reported that animals with HPL...
Altered apoptosis and proliferation in milk cells and PBMc from BLV-infected bovines with different proviral loads: Possible role of the BCL-2 family proteins, TNF-alpha, and receptors.
Bovines infected by bovine leukemia virus (BLV) are characterized by presenting low proviral load (LPL) or high proviral load (HPL). It is reported that animals with HPL in peripheral blood mononuclear cells (PBMCs) present a decrease in apoptosis, an increase in viability and the proliferation rate, while animals that maintain an LPL have an intrinsic ability to control the infection, presenting an increased apoptosis rate of their PBMCs. However, there is little information on the effect of BLV on these mechanisms when the virus infects somatic milk cells (SC). This study investigates the mechanisms underlying apoptosis in milk and blood from BLV-infected animals with HPL and LPL. Relative levels of mRNA of tumor necrosis factor-α (TNF-α), TNF receptor 1 (TNF-RI), TNF receptor 2 (TNF-RII), anti-apoptotic B-cell lymphoma 2 protein (Bcl-2), and pro-apoptotic Bcl-2-like protein 4 (Bax) were measured in SC and PBMCs using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay. A significant decrease in the expression of TNF-α in SC from HPL animals vs non-infected bovines was observed, but the infection in SC with BLV did not show a modulation on the expression of TNF receptors. A significant increase in TNF-RI expression in PBMCs from HPL bovines compared to LPL bovines was observed. No significant differences in PBMCs between HPL and LPL compared to non-infected animals concerning TNF-α, TNF-RI, and TNF-RII expression were found. There was a significant increase of both Bcl-2 and Bax in SC from LPL compared to non-infected bovines, but the Bcl-2/Bax ratio showed an anti-apoptotic profile in LPL and HPL bovines compared to non-infected ones. Reduced mRNA expression levels of Bax were determined in the PBMCs from HPL compared to LPL subjects. In contrast, BLV-infected bovines did not differ significantly in the mRNA expression of Bax compared to non-infected bovines. Our data suggest that the increased mRNA expression of Bax corresponds to the late lactation state of bovine evaluated and the exacerbated increase of mRNA expression of Bcl-2 may be one of the mechanisms for the negative apoptosis regulation in the mammary gland induced by BLV infection. These results provide new insights into the mechanism of mammary cell death in HPL and LPL BLV-infected bovine mammary gland cells during lactation.
Topics: Animals; Cattle; Female; Apoptosis; bcl-2-Associated X Protein; Cattle Diseases; Cell Proliferation; Enzootic Bovine Leukosis; Leukemia Virus, Bovine; Leukocytes, Mononuclear; Milk; Proviruses; Receptors, Tumor Necrosis Factor, Type II; RNA, Messenger; Tumor Necrosis Factor-alpha
PubMed: 38154260
DOI: 10.1016/j.vetimm.2023.110703 -
Frontiers in Immunology 2023HTLV-1 infection is a neglected disease, despite estimates of 10 million people infected worldwide and producing life-threatening illnesses in 10% of carriers. Sexual...
BACKGROUND
HTLV-1 infection is a neglected disease, despite estimates of 10 million people infected worldwide and producing life-threatening illnesses in 10% of carriers. Sexual transmission is the main route of contagion. However, HTLV-1 is not listed among sexually transmitted infections (STIs).
METHODS
Serum from all consecutive individuals who had attended six STI clinics across Spain during the last 12 months were tested for HTLV antibodies using a commercial enzyme immunoassay (EIA). Reactive samples were confirmed by immunoblot.
RESULTS
A total of 2,524 samples were examined. The majority (1,936; 76.7%) belonged to men, of whom 676 (34.9%) were men who have sex with men (MSM) receiving HIV pre-exposure prophylaxis. Although native Spaniards predominated (1,470; 58.2%), up to 593 (23.5%) came from Latin America and 139 (5.5%) were African. A total of 26 individuals were initially EIA reactive and immunoblot confirmed 5 as HTLV-1 and 7 as HTLV-2. All but one HTLV-1+ case came from Latin America. Three were men and two were women. Among Latin Americans, the HTLV-1 seroprevalence was 0.67%. In contrast, all seven HTLV-2+ were native Spaniards and former injection drug users, and all but one were HIV+.
CONCLUSION
The rate of HTLV infection among individuals with STIs in Spain is 0.5%, which is greater than in the general population. These results support the introduction of universal HTLV screening in persons who attend clinics for STIs.
Topics: Male; Humans; Female; Homosexuality, Male; Spain; Seroepidemiologic Studies; Sexual and Gender Minorities; Deltaretrovirus Infections; Human T-lymphotropic virus 1; Sexually Transmitted Diseases; HIV Infections
PubMed: 38143748
DOI: 10.3389/fimmu.2023.1277793 -
The Journal of Veterinary Medical... Feb 2024Enzootic bovine leukosis (EBL) is B-cell lymphoma in cattle caused by bovine leukemia virus (BLV) infection. The incidence of EBL has been increasing since 1998 in...
Enzootic bovine leukosis (EBL) is B-cell lymphoma in cattle caused by bovine leukemia virus (BLV) infection. The incidence of EBL has been increasing since 1998 in Japan, resulting in significant economic losses for farms. The BLV genome integrates with the host genome as provirus, leading to sustainably infection. Although most of the BLV-infected cattle are aleukemic, some cattle cause persistent lymphocytosis (PL) and subsequently develop EBL. Recent reports suggest the association between the risk for the transmission of BLV and the developing EBL and the proviral load (PVL) in BLV-infected cattle, which cannot measure readily in the field. This study aims to build a statistical model for predicting PVL of BLV-infected asymptomatic or PL cattle based on data accessible in the field. Five negative binomial regression models with different linear predictors were built and compared for the predictability of PVL. Consequently, the model with two explanatory variables (age in months and logarithm of lymphocyte count) was selected as the best model. The model can be used in the field as a cost-beneficial supporting tool to estimate the risk of transmission of BLV and developing EBL in infected cattle.
Topics: Cattle; Animals; Leukemia Virus, Bovine; Proviruses; Enzootic Bovine Leukosis; Lymphocyte Count; Models, Statistical; Cattle Diseases
PubMed: 38123328
DOI: 10.1292/jvms.23-0157 -
Virology Journal Dec 2023Human T-lymphotropic virus 1 (HTLV-1) is associated with the development of several pathologies and chronic infection in humans. The inefficiency of the available...
BACKGROUND
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.
METHODS
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.
RESULTS
T CD4 and T CD8 lymphocytes cells stimulated by HBZ-peptides (HBZ and HBZ) 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/CD62L), 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.
CONCLUSIONS
Our results highlight the potential of the HBZ multiepitope protein expressed from plasmid DNA and a poxviral vector as candidates for therapeutic vaccine.
Topics: Mice; Humans; Animals; Human T-lymphotropic virus 1; CD8-Positive T-Lymphocytes; Granzymes; Tumor Necrosis Factor-alpha; Vaccines, DNA; Viral Proteins; Vaccinia virus; DNA; Basic-Leucine Zipper Transcription Factors; Retroviridae Proteins
PubMed: 38115107
DOI: 10.1186/s12985-023-02264-z