Epitope-based universal vaccine for Human T-lymphotropic virus-1 (HTLV-1).
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ABSTRACT:
SUBMITTER: Raza MT
PROVIDER: S-EPMC8018625 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human T-lymphotropic virus (HTLV), a group of retroviruses belonging to the oncovirus family, has long been associated with various inflammatory and immunosuppressive disorders. At present, there is no approved vaccine capable of effectively combating all the highly pathogenic strains of HTLV that makes this group of viruses a potential threat to human health. To combat the devastating impact of any potential future outbreak caused by this virus group, our study employed a reverse vaccinology approach to design a novel polyvalent vaccine targeting the highly virulent subtypes of HTLV. Moreover, we comprehensively analyzed the molecular interactions between the designed vaccine and corresponding Toll-like receptors (TLRs), providing valuable insights for future research on preventing and managing HTLV-related diseases and any possible outbreaks. The vaccine was designed by focusing on the envelope glycoprotein gp62, a crucial protein involved in the infectious process and immune mechanisms of HTLV inside the human body. Epitope mapping identified T cell and B cell epitopes with low binding energies, ensuring their immunogenicity and safety. Linkers and adjuvants were incorporated to enhance the vaccine's stability, antigenicity, and immunogenicity. Initially, two vaccine constructs were formulated, and among them, vaccine construct-2 exhibited superior solubility and structural stability. Molecular docking analyses also revealed strong binding affinity between the vaccine construct-2 and both targeted TLR2 and TLR4. Molecular dynamics simulations demonstrated enhanced stability, compactness, and consistent hydrogen bonding within TLR-vaccine complexes, suggesting a strong binding affinity. The stability of the complexes was further corroborated by contact, free energy, structure, and MM-PBSA analyses. Consequently, our research proposes a vaccine targeting multiple HTLV subtypes, offering valuable insights into the molecular interactions between the vaccine and TLRs. These findings should contribute to developing effective preventive and treatment approaches against HTLV-related diseases and preventing possible outbreaks. However, future research should focus on in-depth validation through experimental studies to confirm the interactions identified in silico and to evaluate the vaccine's efficacy in relevant animal models and, eventually, in clinical trials.
| S-EPMC10490984 | biostudies-literature
Project description:We conducted phylogenetic analyses and an estimation of coalescence times for East Asian strains of HTLV-1. Phylogenetic analyses showed that the following three lineages exist in Japan: "JPN", primarily comprising Japanese isolates; "EAS", comprising Japanese and two Chinese isolates, of which one originated from Chengdu and the other from Fujian; and "GLB1", comprising isolates from various locations worldwide, including a few Japanese isolates. It was estimated that the JPN and EAS lineages originated as independent lineages approximately 3,900 and 6,000 years ago, respectively. Based on archaeological findings, the "Out of Sunda" hypothesis was recently proposed to clarify the source of the Jomon (early neolithic) cultures of Japan. According to this hypothesis, it is suggested that the arrival of neolithic people in Japan began approximately 10,000 years ago, with a second wave of immigrants arriving between 6,000 and 4,000 years ago, peaking at around 4,000 years ago. Estimated coalescence times of the EAS and JPN lineages place the origins of these lineages within this 6,000-4,000 year period, suggesting that HTLV-1 was introduced to Japan by neolithic immigrants, not Paleo-Mongoloids. Moreover, our data suggest that the other minor lineage, GLB1, may have been introduced to Japan by Africans accompanying European traders several centuries ago, during or after "The Age of Discovery." Thus, the results of this study greatly increase our understanding of the origins and current distribution of HTLV-1 lineages in Japan and provide further insights into the ethno-epidemiology of HTLV-1.
| S-EPMC3598069 | biostudies-literature
Project description:Human T-cell Leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are pathogenic retroviruses that infect humans and cause severe hematological and neurological diseases. Both viruses have simian counterparts (STLV-1 and STLV-2). STLV-3 belongs to a third group of lymphotropic viruses which infect numerous African monkeys species. Among 240 Cameroonian plasma tested for the presence of HTLV-1 and/or HTLV-2 antibodies, 48 scored positive by immunofluorescence. Among those, 27 had indeterminate western-blot pattern. PCR amplification of pol and tax regions, using HTLV-1, -2 and STLV-3 highly conserved primers, demonstrated the presence of a new human retrovirus in one DNA sample. tax (180 bp) and pol (318 bp) phylogenetic analyses demonstrated the strong relationships between the novel human strain (Pyl43) and STLV-3 isolates from Cameroon. The virus, that we tentatively named HTLV-3, originated from a 62 years old Bakola Pygmy living in a remote settlement in the rain forest of Southern Cameroon. The plasma was reactive on MT2 cells but was negative on C19 cells. The HTLV 2.4 western-blot exhibited a strong reactivity to p19 and a faint one to MTA-1. On the INNO-LIA strip, it reacted faintly with the generic p19 (I/II), but strongly to the generic gp46 (I/II) and to the specific HTLV-2 gp46. The molecular relationships between Pyl43 and STLV-3 are thus not paralleled by the serological results, as most of the STLV-3 infected monkeys have an "HTLV-2 like" WB pattern. In the context of the multiple interspecies transmissions which occurred in the past, and led to the present-day distribution of the PTLV-1, it is thus very tempting to speculate that this newly discovered human retrovirus HTLV-3 might be widespread, at least in the African continent.
| S-EPMC1142341 | biostudies-literature
Project description:There is a need to develop a universal vaccine against influenza virus infection to avoid developing new formulations of a seasonal vaccine each year. Many of the vaccine strategies for a universal vaccine target strain-conserved influenza virus proteins, such as the matrix, polymerase, and nucleoproteins, rather than the surface hemagglutinin and neuraminidase proteins. In addition, non-disease-causing viral vectors are a popular choice as a delivery system for the influenza virus antigens. As a proof-of-concept, we have designed a novel influenza virus immunogen based on the NP backbone containing human T cell epitopes for M1, NS1, NP, PB1 and PA proteins (referred as NPmix) as well as a construct containing the conserved regions of influenza virus neuraminidase (N-terminal) and hemagglutinin (C-terminal) (referred as NA-HA). DNA vectors and vaccinia virus recombinants expressing NPmix (WR-NP) or both NPmix plus NA-HA (WR-flu) in the cytosol were tested in a heterologous DNA-prime/vaccinia virus-boost vaccine regimen in mice. We observed an increase in the number of influenza virus-specific IFN?-secreting splenocytes, composed of populations marked by CD4(+) and CD8(+) T cells producing IFN? or TNF?. Upon challenge with influenza virus, the vaccinated mice exhibited decreased viral load in the lungs and a delay in mortality. These findings suggest that DNA prime/poxvirus boost with human multi-epitope recombinant influenza virus proteins is a valid approach for a general T-cell vaccine to protect against influenza virus infection.
| S-EPMC3187825 | biostudies-literature
Project description:Serological screening for human T-lymphotropic virus type 1 (HTLV-1) parallels the standard screening process for human immunodeficiency virus (HIV), in which samples found positive by enzyme-linked immunosorbent assay (ELISA) are confirmed with a modified Western blot procedure. There are a significant number of cases in which HTLV-1/2 ELISA-positive specimens demonstrate an incomplete banding pattern on this Western blot. Individuals providing these atypical antibody responses are categorized as seroindeterminate for HTLV-1/2. Although HTLV-1 genomic sequences are readily detectable in the peripheral blood lymphocytes (PBL) of seropositive individuals, previous studies have repeatedly demonstrated that PBL from the vast majority of HTLV-1/2 seroindeterminate individuals are PCR negative for HTLV-1. As a result, identification of the agent responsible for this indeterminate reactivity has been of interest. We have generated an HTLV-1-positive B-cell line (SI-1 B) from one of these seroindeterminate individuals. Previous screening for HTLV-1 in PBL from this patient had been routinely negative by primary PCR; however, HTLV-1 tax had been periodically detected by nested PCR. DNA sequence data generated with genomic DNA from the SI-1 B cell line and HTLV-1-specific primers demonstrated the presence of a full-length viral genome with >97% homology to the Cosmopolitan form of HTLV-1. A 12-bp deletion was identified in the 3'-gag/5'-prot region, which would predict translation of altered or nonfunctional proteins from these genes. We propose that this HTLV-1/2-seroindeterminate patient is infected with a prototypic form of HTLV-1 at an extremely low viral load and that this finding may explain HTLV-1/2 seroindeterminate reactivity in at least a subset of these individuals.
| S-EPMC111698 | biostudies-literature
Project description:Provirus mutations of human T-lymphotropic virus 1 (HTLV-1), mostly the lack of the 5' long terminal repeat (LTR) genomic region, have been described and associated with severe adult T cell leukemia/lymphoma (ATLL), non-sense point mutations with low proviral load, and Western blotting indeterminate results. Until now, no information concerning provirus mutations of HTLV-2 and its consequences, as well as those of HTLV-1/2 in HIV-coinfected individuals, had been described. Therefore, we searched for these mutations in provirus samples of 44 HIV/HTLV-1- and 25 HIV/HTLV-2-coinfected individuals. Using protocols well established for amplification and sequencing of segments of the LTR, env, and tax regions, we searched for defective type 1 particles that retain LTRs and lack internal sequences and type 2 particles that lack the 5'LTR region. In addition, using as references the prototypes ATK (HTLV-1) and Mo (HTLV-2), we searched for point mutations in the LTR and synonyms and nonsynonymous mutations and non-sense mutations in env and tax regions. Defective HTLV-1 and HTLV-2 provirus type 1 or 2 was detected in 31.8% of HIV/HTLV-1- and 32.0% of HIV/HTLV-2-coinfected individuals. Synonymous and nonsynonymous mutations were identified mostly in HTLV-2 and associated with lower levels of specific antibodies. No non-sense mutations that resulted in premature termination of Env and Tax proteins were detected. On the contrary, mutation in the stop codon of Tax2a produced a long protein characteristic of the HTLV-2c subtype. The clinical significance of these mutations in coinfected individuals remains to be defined, but they confirmed the lower sensitivity of serological and molecular diagnostic tests in HIV/HTLV-1/2 coinfections.IMPORTANCE HTLV-1 and HTLV-2 are endemic to Brazil, and they have different effects in HIV/AIDS disease progression. HIV/HTLV-1 has been described as accelerating the progression to AIDS and death, while HIV/HTLV-2 slows the progression to AIDS. Provirus mutations of HTLV-1 were implicated in severe leukemia development and in problems in the diagnosis of HTLV-1; in contrast, provirus mutations of HTLV-2 had not been confirmed and associated with problems in HTLV-2 diagnosis or disease outcome. Nevertheless, data obtained here allowed us to recognize and understand the false-negative results in serologic and molecular tests applied for HTLV-1 and HTLV-2 diagnosis. Defective proviruses, as well as synonymous and nonsynonymous mutations, were associated with the diagnosis deficiencies. Additionally, since HIV-1 and HTLV-1 infect the same cells (CD4 positive), the production of HIV-1 pseudotypes with HTLV-1 envelope glycoprotein during HIV/HTLV-1 coinfection cannot be excluded. Defective provirus of HTLV-2 and Tax2c is speculated to influence progression to AIDS.
| S-EPMC7529439 | biostudies-literature
Project description:Both Human T-lymphotropic virus type 1 (HTLV-1) and hepatitis C virus (HCV) are endemic in Brazil. In Salvador, the capital of the state of Bahia, 2% and 1.5% of the general population is infected with HTLV-1 or HCV. This study aimed to estimate the prevalence and the distribution of HTLV/HCV coinfection in Bahia. This cross-sectional study was conducted at the Central Laboratory of Public Health for the state of Bahia (LACEN-BA). All samples in the LACEN database submitted to serological testing for anti-HCV (chemiluminescence) and anti-HTLV-1/2 (chemiluminescence/ELISA and Western blot) from 2004 to 2013 were included. Infection rate was expressed as the number of infected individuals per 100,000 inhabitants in a given municipality; municipalities were grouped by microregion for further analysis. A total of 120,192 samples originating from 358 of the 417 municipalities in Bahia (85.8%) were evaluated. The overall HCV coinfection rate in HTLV-positive was 14.31% [2.8 (ranging from 0.4 to 8.0) per 100,000 inhabitants.] Twenty-one (5%) of the municipalities reported at least one case of HTLV/HCV coinfection. Most cases (87%) were concentrated in three microregions (Salvador: 79%, Ilhéus/Itabuna: 5%, Porto Seguro: 3%). Coinfection occurred more frequently in males (51%) with a mean age of 59 [(IQR): 46-59] years. HTLV/HCV coinfection in the state of Bahia was more frequently found among males living in the microregions of Salvador, Ilhéus/Itabuna and Porto Seguro, all of which are known to be endemic for HTLV infection.
| S-EPMC7373273 | biostudies-literature
Project description:Endemic areas of human T-lymphotropic virus type 1 (HTLV-1) have been reported in Japan as well as tropical Africa, Central and South America and Melanesia. The existence of two subgroups, i.e., the transcontinental and Japanese subgroups, was reported in Japan. In the present study, we provide data on the ratio of the two subgroups in each endemic area and infection foci and examine the distribution of HTLV-1 in Japan and neighboring areas. A 657 bp fragment of env region of HTLV-1 proviral genome was successfully amplified for 183 HTLV-1 positive DNA samples. The subgroup determination was done by RFLP reactions using endonucleases HpaI and HinfI. The northern part of mainland Kyushu, represented by Hirado and Kumamoto, was monopolized by the Japanese subgroup, while the transcontinental subgroup ranged from 20 to 35% in the Pacific coast areas of Shikoku (Kochi), the Ryukyu Archipelago (Kakeroma and Okinawa) and Taiwan. An interesting finding in the present study is the presence of the transcontinental subgroup in Kochi, suggesting the endemicity of the transcontinental subgroup along the Kuroshio Current.
| S-EPMC3475314 | biostudies-literature
Project description:BackgroundHTLV-1 infection is endemic in Brazil. About 1 to 2% of the Brazilian population is estimated to be infected, but most infected HTLV-1 individuals do not know about their own infection, which favors the continuity of sexual and vertical virus transmission. In addition, HTLV-1 associated central nervous system diseases and their pathophysiologic mechanisms are not fully understood. This study aimed to evaluate the correlation of spinal cord metabolism, viral and inflammatory profiles with features of neurological presentation in HTLV-1 infected individuals.MethodologyThis is a cross-sectional study of a cohort including 48 HTLV-1 infected individuals clinically classified as asymptomatic-AG (N = 21), symptomatic-SG (N = 11) and HAM/TSP-HG (N = 16) and a nested case-control study with HTLV-1 infected individuals-HIG (N = 48) and HTLV-1 non infected controls-CG (N = 30) that had their spinal cord analysed by Positron Emission Tomography with 18F-Fluordeoxyglucose (18F-FDG PET/CT). HTLV-1 infected individuals had 18F-FDG PET/CT results analyzed with clinical and demographic data, proviral load, cytokines and chemokines in the blood and cerebrospinal fluid (CSF).Principal findings18F-FDG PET/CT showed hypometabolism in the thoracic spinal cord in HTLV-1 infected individuals. The method had an accuracy of 94.4% to identify HAM/TSP. A greater involvement of the thoracic spinal cord was observed, although hypometabolism was also observed in the cervical spinal cord segment in HTLV-1 infected individuals. Individuals with HAM/TSP showed a pro-inflammatory profile in comparison to asymptomatic and symptomatic groups, with a higher level of Interferon-inducible T-cell alpha chemoattractant (ITAC/CXCL11), IL-6, IL-12p70 in the plasma; and ITAC, IL-4, IL-5, IL-8 (CXCL8) and TNF-alpha in the CSF. Using regression, thoracic spinal cord SUV (standardized uptake value) and CSF ITAC level were identified as the HAM/TSP predictors in the multivariate model.Conclusions18F-FDG PET/CT imaging showed spinal cord hypometabolism in most HTLV-1 infected individuals, even in the asymptomatic HTLV-1 group. Thoracic spinal cord hypometabolism and CSF-ITAC levels were identified predictors of HAM/TSP.SignificanceOur findings suggested that in most HTLV-1 infected individuals there was compromise of central nervous system (CNS) structures despite of the lack of clinical symptoms. To explain the found hypometabolism, the role of microcirculatory and metabolic factors in the pathogenesis of neurological diseases associated with HTLV-1 infection must be further investigated. It is paramount to evaluate the central nervous function and to compare the performance among HTLV-1 infected individuals considered asymptomatic to the uninfected controls.
| S-EPMC6128630 | biostudies-literature
Project description:BACKGROUND: A study was undertaken to investigate the pathogenesis of pulmonary involvement in human T lymphotropic virus type I (HTLV-I) carriers. METHODS: The bronchoalveolar lavage (BAL) cell profile of 30 HTLV-I carriers (15 asymptomatic HTLV-I carriers (AHCs) and 15 symptomatic HTLV-I carriers (SHCs)) with chronic inflammatory diseases of respiratory tract and eight patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) was investigated. The HTLV-I proviral deoxyribonucleic acid (DNA) load in peripheral blood mononuclear cells (PBMCs) and BAL fluid from HTLV-I carriers was estimated using the quantitative polymerase chain reaction method and the correlation between the lymphocyte number in BAL fluid and the HTLV-I proviral DNA load in PBMCs and BAL fluid was examined. RESULTS: The percentage of lymphocytes in BAL fluid was increased (>18%) in 11 of 30 HTLV-I carriers although there was no significant difference compared with control subjects. In HTLV-I carriers the lymphocyte number in BAL fluid correlated well with the copy number of HTLV-I proviral DNA in PBMCs. In addition, the copy number of HTLV-I proviral DNA in BAL fluid correlated well with the number of lymphocytes (both CD4+ and CD8+ cells) in BAL fluid. CONCLUSIONS: These findings suggest that pulmonary lymphocytosis can occur in a subset of HTLV-I carriers without HAM/TSP and that the increased HTLV-I proviral DNA load may be implicated in the pathogenesis of pulmonary involvement in HTLV-I carriers.
| S-EPMC1747290 | biostudies-other