Novel insights into human T-lymphotropic virus type-1 (HTLV-1) pathogenesis-host interactions in the manifestation of HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T-lymphotropic virus type-1 (HTLV-1) was the first discovered human oncogenic retrovirus, the etiological agent of two serious diseases have been identified as adult T-cell leukaemia/lymphoma malignancy and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a debilitating chronic neuro-myelopathy. Despite more than 40 years of molecular, histopathological and immunological studies on HTLV-1-associated diseases, the virulence and pathogenicity of this virus are yet to be clarified. The reason why the majority of HTLV-1-infected individuals (∼95%) remain asymptomatic carriers is still unclear. The deterioration of the immune system towards oncogenicity and autoimmunity makes HTLV-1 a natural probe for the study of malignancy and neuro-inflammatory diseases. Additionally, its slow worldwide spreading has prompted public health authorities and researchers, as urged by the WHO, to focus on eradicating HTLV-1. In contrast, neither an effective therapy nor a protective vaccine has been introduced. This comprehensive review focused on the most relevant studies of the neuro-inflammatory propensity of HTLV-1-induced HAM/TSP. Such an emphasis on the virus-host interactions in the HAM/TSP pathogenesis will be critically discussed epigenetically. The findings may shed light on future research venues in designing and developing proper HTLV-1 therapeutics.

Production and Evaluation of Ag85B:HspX:hFcγ1 Immunogenicity as an Fc Fusion Recombinant Multi-Stage Vaccine Candidate Against Mycobacterium tuberculosis.

An urgent need is to introduce an effective vaccine against Mycobacterium tuberculosis (M.tb) infection. In the present study, a multi-stage M.tb immunodominant Fcγ1 fusion protein (Ag85B:HspX:hFcγ1) was designed and produced, and the immunogenicity of purified protein was evaluated. This recombinant fusion protein was produced in the Pichia pastoris expression system. The HiTrap-rPA column affinity chromatography purified and confirmed the fusion protein using ELISA and Western blotting methods. The co-localisation assay was used to confirm its proper folding and function. IFN-γ, IL-12, IL-4, and TGF-ß expression in C57BL/6 mice then evaluated the immunogenicity of the construct in the presence and absence of BCG. After expression optimisation, medium-scale production and the Western blotting test confirmed suitable production of Ag85B:HspX:hFcγ1. The co-localisation results on antigen-presenting cells (APCs) showed that Ag85B:HspX:hFcγ1 properly folded and bound to hFcγRI. This strong co-localisation with its receptor can confirm inducing proper Th1 responses. The in vivo immunisation assay showed no difference in the expression of IL-4 but a substantial increase in the expression of IFN-γ and IL-12 (P ≤ 0.02) and a moderate increase in TGF-ß (P = 0.05). In vivo immunisation assay revealed that Th1-inducing pathways have been stimulated, as IFN-γ and IL-12 strongly, and TGF-ß expression moderately increased in Ag85B:HspX:hFcγ1 group and Ag85B:HspX:hFcγ1+BCG. Furthermore, the production of IFN-γ from splenocytes in the Ag85B:HspX:hFcγ1 group was enormously higher than in other treatments. Therefore, this Fc fusion protein can make a selective multi-stage delivery system for inducing appropriate Th1 responses and is used as a subunit vaccine alone or in combination with others.

Pathogenicity and virulence of human T lymphotropic virus type-1 (HTLV-1) in oncogenesis: adult T-cell leukemia/lymphoma (ATLL).

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T lymphocytes caused by human T lymphotropic virus type-1 (HTLV-1) infection. HTLV-1 was brought to the World Health Organization (WHO) and researchers to address its impact on global public health, oncogenicity, and deterioration of the host immune system toward autoimmunity. In a minority of the infected population (3-5%), it can induce inflammatory networks toward HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or hijacking the infected CD4+ T lymphocytes into T regulatory subpopulation, stimulating anti-inflammatory signaling networks, and prompting ATLL development. This review critically discusses the complex signaling networks in ATLL pathogenesis during virus-host interactions for better interpretation of oncogenicity and introduces the main candidates in the pathogenesis of ATLL. At least two viral factors, HTLV-1 trans-activator protein (TAX) and HTLV-1 basic leucine zipper factor (HBZ), are implicated in ATLL manifestation, interacting with host responses and deregulating cell signaling in favor of infected cell survival and virus dissemination. Such molecules can be used as potential novel biomarkers for ATLL prognosis or targets for therapy. Moreover, the challenging aspects of HTLV-1 oncogenesis introduced in this review could open new venues for further studies on acute leukemia pathogenesis. These features can aid in the discovery of effective immunotherapies when reversing the gene expression profile toward appropriate immune responses gradually becomes attainable.

Momordica charantia phytoconstituents can inhibit human T-lymphotropic virus type-1 (HTLV-1) infectivity in vitro and in vivo.

There is an urgent need to find an effective therapy for life-threatening HTLV-1-associated diseases. Bitter melon (Momordica charantia) is considered a traditional herb with antiviral and anticancer properties and was tested in this study on HTLV-1 infectivity. GC-MS analyzed the alcoholic extract. In vitro assay was carried out using transfection of HUVEC cells by HTLV-1-MT2 cell line. The cells were exposed to alcoholic and aqueous extracts at 5,10, and 20 µg/mL concentrations. In vivo, mice were divided into four groups. Three groups were treated with HTLV-1-MT-2 cells as test groups and positive control, and PBS as the negative control group in the presence and absence of M. charantia extracts. Peripheral blood mononuclear cells (PBMCs), mesenteric lymph nodes (MLNs), and splenocytes were collected for HTLV-1-proviral load (PVL) assessment, TaqMan-qPCR. The GC-MS analysis revealed 36 components in M. charantia. The studies showed significant reductions in HTLV-1-PVL in the presence of extract in the HUVEC-treated groups (P = 0.001). Furthermore, the inhibitory effects of extracts on HTLV-1 infected mice showed significant differences in HTLV-1-PVL among M. charantia treated groups with untreated (P = 0.001). The T-cells in MLNs were significantly more susceptible to HTLV-1 than others (P = 0.001). There were significant differences among HTLV-1-infected cells in MLNs and splenocytes (P = 0.001 and 0.046, respectively). Also, aqueous and alcoholic extract-treated groups significantly affected HTLV-1-infected PBMCs (P = 0.002 and 0.009, respectively). M. charantia may have effective antiviral properties. The substantial compound of M. charantia could have inhibitory effects on the proliferation and transmission of HTLV-1 oncovirus.

Role of host immunity and HBx among inactive chronic hepatitis B patients in a highly endemic region.

The hepatitis B virus (HBV) infection has a wide range, from fulminant hepatitis to inactive chronic hepatitis B (ICB) infection. The present study evaluated critical factors in the outcomes of HBV infection in a highly endemic region of Iran (approximately 12% HBV positive). The expression of seven genes involved in host immunity (Foxp3, T-bet, ROR-γt, AKT, CREB, IL-28/or IFN-λ2, and IL-28R) and HBx for viral activities were evaluated using real-time PCR, TaqMan method. A total of 58 subjects were randomly chosen, including 28 ICB and 30 healthy controls (HCs) from the Esfandiar district, South Khorasan province, Iran. The expression index of Foxp3 and ROR-γt was moderately up-regulated in ICBs but did not statistically significant. T-bet expression in ICB patients was significantly higher than in HCs (p = 0.004). Furthermore, evaluating two signalling pathways in Th activation and cell survival showed that the CREB pathway was significantly up-regulated in ICB patients compared to HCs (p = 0.006), but the AKT did not differ. In innate immune responses, the IL-28/or IFN-λ2 expression in ICB patients was significantly higher than in the HCs (p = 0.02). Surprisingly, only one ICB patient disclosed HBx expression, which shows deficient virus activity in these patients. The ICB condition seems to result from host immune pressure on HBV activities, up-regulation of T-bet and IFN-λ. The high expression of CREB may prevent Kupffer's pro-inflammatory reactions in the liver. Whereas the absence of HBx expression in ICB patients and, consequently, the inactivity of HBV may also confirm such immune pressure.

Gene expression study of host-human T-cell leukaemia virus type 1 (HTLV-1) interactions: adult T-cell leukaemia/lymphoma (ATLL).

BACKGROUND: In HTLV-1-associated malignant disease, adult T-cell leukaemia/lymphoma (ATLL), the interaction of virus and host was evaluated at the chemokines gene expression level. Also, IL-1ß and Caspase-1 expressions were evaluated to investigate the importance of pyroptosis in disease development and progression. METHODS AND RESULTS: The expression of host CCR6 and CXCR-3 and the HTLV-1 proviral load (PVL), Tax, and HBZ were assessed in 17 HTLV-1 asymptomatic carriers (ACs) and 12 ATLL patients using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR), TaqMan method. Moreover, RT-qPCR, SYBR Green assay were performed to measure Caspase-1 and IL-1ß expression. HTLV-1-Tax did not express in 91.5% of the ATLLs, while HBZ was expressed in all ATLLs. The expression of CXCR3 dramatically decreased in ATLLs compared to ACs (p = 0.001). The expression of CCR6 was lower in ATLLs than ACs (p = 0.04). The mean of PVL in ATLL patients was statistically higher than ACs (p = 0.001). Furthermore, the expression of the IL-1ß between ATLLs and ACs was not statistically significant (p = 0.4). In contrast, there was a meaningful difference between Caspase-1 in ATLLs and ACs (p = 0.02). CONCLUSIONS: The present study indicated that in the first stage of ATLL malignancy toward acute lymphomatous, CXCR3 and its progression phase may target the pyroptosis process. Mainly, HBZ expression could be a novel therapeutic target.

HTLV, a multi organ oncovirus.

Human T lymphotropic virus (HTLV-I) is a retrovirus that has been recognized as a causative agent of two crucidal diseases, HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) and Adult T cell Leukemia-Lymphoma (ATLL). The virus not only induces those diseases in a small proportion of HTLV-I carriers (3-5%) but also it is associated with other diseases such as HTLV-I-Associated Arthropathy (HAAP), Cutaneous T Cell Lymphoma (CTCL), Graves' disease, uveitis, polymyositis, chronic respiratory diseases, lymphadenitis and dermatitis. Furthermore, HTLV related and accelerated disorders were more investigated, and the factors that might implicate in the development or progression of diseases have been discussed. We founded 13 categories of non-associated disease in studies such as Reproductive Disorders, Coronary Artery Disease (CAD), non -ATLL lymphoma, Co-infection, non-HAM/TSP neurological associated disease, non ATLL cutaneous associated disease, Autoimmune-Inflammatory related disease, Kidney disease, Liver disease, Respiratory disease, TB disease and Thyroid disease. With regard to the reviewed studies suggested HTLV-I disorders can divide into three manifests; related, accelerated and associated disease. However, interaction between HTLV-I infection and host immune response was complicated and vague. Some infectious patients indicated the involvement of inflammatory response of immune system, but in other individuals function of anti-inflammatory elements was observed. For a better understanding of this classification, more systematic studies should be designed and need to provide a global network to control and prevent HTLV affiliated diseases.

HTLV-1 oncovirus-host interactions: From entry to the manifestation of associated diseases.

Human T lymphotropic virus type-1 (HTLV-1) is a well-known human oncovirus, associated with two life-threatening diseases, adult T cell leukaemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The study of this oncogenic virus is significant from two different aspects. First, HTLV-1 can be considered as a neglected public health problem, which may spread slowly worldwide. Second, the incidence of HTLV-1 associated diseases due to oncogenic effects and deterioration of the immune system towards autoimmune diseases are not fully understood. Furthermore, knowledge about viral routes of transmission is important for considering potential interventions, treatments or vaccines in endemic regions. In this review, novel characteristics of HTLV-1, such as the unusual infectivity of virions through the virological synapse, are discussed in the context of the HTLV-1 associated diseases (ATL and HAM/TSP).

Detection of Isoniazid and Rifampin Resistance in Mycobacterium tuberculosis Clinical Isolates from Sputum Samples by High-Resolution Melting Analysis.

The effective management of multidrug-resistant tuberculosis (MDR-TB) and the need for rapid and accurate screening of rifampin (RIF) and isoniazid (INH)-resistant Mycobacterium tuberculosis (Mtb) isolates are the most fundamental and difficult challenges facing the global TB control. The present study aimed to compare the diagnostic accuracy of high-resolution melting-curve analysis (HRMA) in comparison to multiplex allele-specific PCR (MAS-PCR) and xpert MTB/RIF as well as the conventional drug-susceptibility test (DST) and gene sequencing for the detection of INH and RIF resistance in the Mtb isolates. In the present study, a total of 431 Mtb isolates including 11 MDR (%2.55), 7 INH resistance (%1.62), two RIF resistance (%0.46), and 411 sensitive isolates were phenotypically confirmed. HRMA assay identified katG gene mutations and the mabA-inhA promoter region in 15 of 18 INH-resistant samples and rpoB gene mutations were successfully evaluated in 11 out of 13 RIF-resistant samples. The sensitivity and specificity of the HRMA method were 83.3% and 98.8% for INH and 84.6% and 99% for RIF, respectively. The most common mutation in RIF-resistance-determining region (RRDR) occurred at codon 531 (TCG → TTG)(84.6%) and then at codon 513 (CAA → GTA)(7.6%) and 526 (CAC → TAC) (7.6%), which resulted in the amino-acid changes. Also, 88.8% of INH-resistant samples had mutations in the katG gene and the mabA-inhA promoter region, of which the highest mutation occurred at codon 315 (AGC → ACC) of the katG gene. In conclusion, all these results indicated that the sensitivity and specificity of the HRM method were increased when the katG gene and the mabA-inhA promoter region were used as a target.

Concordance assessment between self-reports of substance use and urinalysis: A population-based study in Mashhad, Iran.

BACKGROUND: Few studies have addressed the validity of self-reports of substance use in Iran. This study was conducted to evaluate concordance between self-reported data on drug use and urinalysis results in an adult population in Mashhad as the second most populous city in Iran. METHODS: This population-based study recruited 2142 Mashhad residents aged over 16 years. The data were obtained from a study conducted in 2015 on the prevalence of chronic kidney disease (CKD) in an adult population in Mashhad. The participants were selected using multistage stratified cluster sampling. To evaluate the validity, the participants' responses to a single-question screening test of drug use were compared with their urinalysis results. The sensitivity, specificity, and positive and negative predictive values of the self-reports were also assessed. RESULTS: The prevalence of drug use was found to be 2.33% (95% CI: 1.75-3.09) based on the self-reported data and 17.74% (95% CI: 16.15-19.43) based on the urinalysis results. Opioids were the most prevalent form of drug used and the self-reports indicated low validity (sensitivity = 12.63%, 95% CI: 9.54-16.49). The women were found more predisposed than the men to misreporting their drug use. DISCUSSION: In line with other studies in Iran, the validity of the self-reports of drug use was found to be low. Policymakers should therefore avoid relying only on self-reported data to evaluate the effectiveness of interventions and preventive strategies.It is recommended that further in-depth studies be conducted to address the factors affecting the validity of self-reports in Iranian populations.

Evaluating mRNA expression of tax, B chain of PDGF and PDGF-ß receptors as well as HTLV-I proviral load in ATL patients and healthy carriers.

Adult T-cell leukemia (ATL) is a life-threatening malignant neoplasm of CD4+ T cells resulted from human T-cell leukemia virus type I (HTLV-I). Tax1 protein of HTLV-I can induce malignant proliferation of T-cells by modulating the expression of growth factors such as platelet-derived growth factor (PDGF). Here, we aimed to investigate the proviral load (PVL) of HTLV-I in ATL and also to evaluate the mRNA expression of B chain of PDGF and PDGF-ß receptors in ATL patients and HTLV-I-infected healthy carriers. To this end, peripheral blood mononuclear cells (PBMCs) were isolated by using Ficoll-Histophaque density centrifugation. The mean of HTLV-I PVL in ATL patients (42,759 ± 15,737 copies/104 cells [95% CI, 9557-75962]) was significantly (p = .01) higher than that in healthy carriers (650 ± 107 copies/104 cells [95% CI, 422-879], respectively. The HTLV-I PVL in ATL patients exhibited a significant correlation with PBMC count (R = .495, p = .001). The mRNA expression of Tax, B chain of PDGF, and PDGF-ß receptor genes was significantly higher in healthy carriers than in patients with ATL. In conclusion, the expression of the canonical PDGFß and its receptor, and their correlation with Tax expression cannot be a suitable indicator and/or prognostic factor for progression of ATL in HTLV-I carriers.

Local and systemic gene expression levels of IL-10, IL-17 and TGF-ß in active ocular toxoplasmosis in humans.

BACKGROUND: To compare mRNA expression of interleukin 10 (IL-10), interleukin 17 (IL-17) and Transforming Growth Factor-ß (TGF-ß) in aqueous humor (AH) and peripheral blood mononuclear cells (PBMCs) in human ocular toxoplasmosis (OT) and controls. METHOD: RNA isolation, cDNA synthesis and real-time polymerase chain reaction were performed on AH sediments and PBMCs of 16 patients with active OT and 21 controls at the Khatam-al-Anbia Eye Hospital, Iran. For comparison, Mann Whitney U test was used at a discrimination level of p < 0.05. Pearson and Spearman rank correlation test were applied for correlation with clinical parameters. RESULTS: The expression for IL-10 and IL-17 in the AH was 3.7- and 88.0-fold higher in OT than in controls (P = 0.04 and P = 0.03, respectively) whereas that of TGF-ß was 7.7-fold lower (P < 0.001). The expression levels for these cytokines in PBMC followed a similar pattern (IL-10 13.8-fold down-regulated (P = 0.001), IL-17 with 1.9-fold insignificantly upregulated (p = 0.43), TGF-ß 452.8-fold down-regulated (P = 0.002). Compared to PBMC, IL-10 coding mRNA was 1876-fold higher in the almost cell-free AH in OT (39.2-fold in controls), IL-17 coding mRNA was 9.4-fold higher (17.7-fold down-regulated in controls), and that coding for TGF-ß 207-fold higher in OT (7x105-fold in controls). The expression for IL-10, IL-17 and TGF-ß in AH thus followed an opposite pattern compared to that in PBMC. CONCLUSION: OT induces a highly-specific local immunoregulatory process as evidenced by an intraocular up-regulation of IL-10 and down-regulation of TGF-ß mRNA. This could indicate an attempt to prevent unnecessary tissue damage which is in line with a moderate local mRNA up-regulation for IL-17 which seems sufficient to control parasite proliferation. That this regulation is opposite to that in PBMC may be linked to intraocular immune deviation in the course of disease.

Rapid and label-free electrochemical DNA biosensor based on a facile one-step electrochemical synthesis of rGO-PPy-(L-Cys)-AuNPs nanocomposite for the HTLV-1 oligonucleotide detection.

Human T cell leukemia virus type 1 (HTLV-1) as the first human retrovirus is currently a serious endemic health challenge. Despite the use of assorted molecular or serological assays for HTLV-1 detection, there are several limitations due to the lack of a confirmatory test that may affect the accuracy of the results. Herein, a novel label-free biosensor for the detection of HTLV-1 Tax gene has been reported. An electrochemical facile ecofriendly synthesis method has been demonstrated based on a synthesis of nanocomposite of reduced graphene oxide, polypyrrole, and gold nanoparticles (rGO-PPy-(l-Cys)-AuNPs) deposited on the surface of screen-printed carbon electrode. Electrochemical techniques were used to characterize and study the electrochemical behavior of the rGO-PPy-(l-Cys)-AuNPs, which exhibited a stable reference peak at 0.21 V associated with hybridization forms by applying the differential pulse voltammetry. The designed DNA biosensor presented a wide linear range from 0.1 fM to 100 µM and a low detection limit of 20 atto-molar. The proposed biosensor presented in this study provides outstanding selectivity, sensitivity, repeatability, and reproducibility.

The IL-18, IL-12, and IFN-γ expression in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, HTLV-1 carriers, and healthy subjects.

Interleukin (IL)-12, IL-18, and interferon gamma (IFN-γ) can induce Th1-inflammatory responses in favor of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) manifestation. In this study, the gene expression and plasma levels of these cytokines were evaluated. The peripheral blood mononuclear cells (PBMCs) in 20 HAM/TSP patients, 21 asymptomatic carriers (ACs), and 21 healthy subjects (HSs) were assessed for the expression of IL-18, IL-12, and IFN-γ, using qRT-PCR. The plasma level of IL-18 and IFN-γ were measured by an ELISA method. The mean of HTLV-1 proviral load (PVL) in the HAM/TSPs was 1846.59 ± 273.25 and higher than ACs at 719.58 ± 150.72 (p = 0.001). The IL-12 was considerably expressed only in nine ACs, five HAM/TSPs, and all HSs. Furthermore, the gene expression and plasma levels of IL-18 were lower in the HTLV-1-positive group than the control group (p = 0.001 and 0.012, respectively); however, there was no significant difference between the ACs and HAM/TSPs. The IFN-γ level was higher in the HTLV-1-positive group (p < 0.001) than HSs. Although there were no correlation between plasma levels of IL-18 and IFN-γ with PVL in the ACs, a positive correlation was observed between plasma IL-18 levels and PVL (r = 0.654, p = 0.002). The highest levels of IFN-γ were observed in the HAM/TSPs which has a significant correlation with HTLV-1-HBZ (r = 0.387, p = 0.05) but not with Tax. However, no significant correlation was found between PVL and proinflammatory pattern. Apart from the IFN-γ as a lymphokine, as a host factor, and HTLV-1-HBZ, as a viral agent, the other proinflammatory monokines or HTLV-1 factors are among the less-effective agents in the maintenance of HAM/TSP.

Status of humoral and cellular immune markers in human T-cell lymphotropic virus type 1 (HTLV-1) asymptomatic carriers in northeastern Iran, Mashhad.

It is estimated that about 10-20 million peoples are infected with human T-cell leukemia virus type 1 (HTLV-1) around the world and suffered from HTLV-related diseases. The present study was aimed to evaluate the cellular immunity, T-cell activation, humoral immunity, and inflammatory response hallmarks which affect HTLV-1-associated disease progression. A total of 78 participants were included in the study, comprising 39 HTLV-1 asymptomatic careers (ACs) and 39 healthy controls. The HTLV-proviral load (PVL) was determined via real-time PCR technique, and anti-HTLV antibody, sIL2R, sCD30, Neoptrin, hs-CRP, IgE, anti-VCA, anti-EBNA, and anti-EA were assessed by ELISA method. Mean PVL in ACs was 352.7 ± 418.7 copies/104 PBMCs. A significant higher level of sIL-2R was observed in ACs (P < 0.0001). Anti-VCA antibody titer in ACs and healthy controls was 80.72 ± 105.95 and 156.05 ± 130.71, respectively (P = 0.007). Intriguingly, suppression in ACs immune response was not observed. Resultantly, HTLV-1 infection has no effect on the humoral immune response in ACs but greater T-cell activation and function cellular responses were detected. Finally, more studies on various immune markers in adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients are greatly needed to illuminate the association of ACs' immune status with the development of the related diseases.

Epigenetics evaluation of the oncogenic mechanisms of two closely related bovine and human deltaretroviruses: A system biology study.

Human T-cell lymphotropic virus (HTLV-1) and bovine leukemia virus (BLV) are oncogenic deltaretroviruses, which are the cause of adult T cell leukemia/lymphoma (ATLL) and enzootic bovine leukosis (EBL), respectively. In this study, to evaluate the virus-host interactions in the manifestation of the associated malignancy, four pooled RNA samples of each host (three RNAs in each sample) were applied to RNA-seq. Differential expression analyses were conducted separately between ATLL and EBL groups, in comparison with the healthy group, to identify functional Gene Ontology (GO) terms and hub genes, using DAVID database and MCODE plugin in Cytoscape software, respectively. A broad range of effective genes, involved in the ATLL and EBL, was up- and downregulated. In the virus side, in both malignancy, Tax was expressed very low, but the HTLV-1-HBZ and BVL-As2 transcripts were highly expressed. Some upregulated hub genes, IL2, TOP2A, MKI67, TP73, MYC, and downregulated FOS gene family (FOS, FOSB, and FOSL2), are similarly activated in both human and bovine hosts, in related cell cycle and growth factors. Taken together, it seems that in preventing the infections and cell transformations, Tax must be targeted as a viral factor, and shared peptide in virological and immunological synapses as host factors. Therefore, in the malignant stages, HBZ and As2 transcripts along with growth factors, particularly IL-2R-γ and T-bet or TOP2A, and MKI67 should be targeted in both hosts. Additional studies at the protein level are necessary to elucidate the more useful targets for the therapy of these life-threatening diseases.

Abnormal vitamin D and lipid profile in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients.

The HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease of host-HTLV-1 interactions. In many virus-associated diseases and multiple sclerosis, the importance of vitamin-D and lipid profile has been demonstrated, thus similarly, their impacts were evaluated in HAM/TSP patients, in this study. Vitamin D and lipid profile were assessed in 120 healthy subjects (HSs), along with a proviral load (PVL) in 91 HAM/TSPs and 169 HTLV-1 carriers (ACs). The mean level of triglyceride and LDL in the HAM/TSPs were higher than HSs (P = 0.008 and 0.008, respectively), but no significant difference has been found between ACs and HSs. However, the level of HDL and vitamin-D in the HAM/TSP subjects were lower than HSs (P = 0.01 and P = 0.006, respectively). In HTLV-1 infected subjects, PVL was statistically associated with cholesterol (R = 0.24, P = 0.038), triglycerides (R = 0.26, P = 0.01) and HDL (R = 0.28, P = 0.001), and in HAM/TSPs there was a strong association between the severity of the disease, as determined by the OMDS and cholesterol (P = 0.01). Furthermore, in the HAM/TSPs, positive correlations between vitamin-D and age (R = 0.23, P = 0.028) and triglycerides (R = 0.38, P = 0.001) were found, also a significant correlation between PVL and LDL (R = 0.21, P = 0.001) and a weak correlation between PVL and OMDS (R = 0.4, P = 0.07) were noted. However, there was no correlation between PVL and urinary disturbance. Furthermore, PVL range of more than 600 copies/104 lymphocytes had a strong correlation with OMDS (P = 0.05), but not with urinary disturbance. It's more likely that HAM/TSP patients have an imbalanced lipid profile and low levels of vitamin D and may represent a potentially useful target for intervention in HTLV-1 associated diseases.

Current approaches for detection of human T-lymphotropic virus Type 1: A systematic review.

BACKGROUND: Human T-lymphotropic virus Type 1 (HTLV-1) is a retrovirus that is endemic in some regions of the world. It is known to cause several diseases like adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Serology and molecular methods have been used to detect this virus. Of these, enzyme-linked immunosorbent assay (ELISA) is used as a primary screening method and this is usually followed by western blotting (WB) and polymerase chain reaction (PCR) methods as confirmatory tests. We conducted a systematic review of the different techniques used in the diagnosis of HTLV-1 infection. MATERIALS AND METHODS: Our search was limited to original papers in the English language from 2010 to 2018 using several databases including Pubmed, Scopus, Google Scholar, Iranmedex, and Scientific Information Database. A manual search of references provided in the included papers was also performed. RESULTS: Of 101 electronically searched citations, 43 met the inclusion criteria. ELISA is commonly used for qualitative and screening detection, and WB and PCR techniques are used to confirm infection. CONCLUSION: Among all the reported methods for detection of HTLV-1, only serological and molecular tests are used as the most common technical assays for HTLV-1. The ELISA assay, without a confirmatory test, has several limitations and affect the accuracy of the results. Owing to the prevalence of HTLV-1 and limitations of the current detection methods, further evaluation of the accuracy of these methods is needed. There are new opportunities for applying novel technological advances in microfluidics, biosensors, and lab-on-a-chip systems to perform HTLV-1 diagnostics.

An insight to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis; evidence from high-throughput data integration and meta-analysis.

BACKGROUND: Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that significantly affected spinal cord, nevertheless, the pathogenesis pathway and reliable biomarkers have not been well determined. This study aimed to employ high throughput meta-analysis to find major genes that are possibly involved in the pathogenesis of HAM/TSP. RESULTS: High-throughput statistical analyses identified 832, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. The protein-protein interactions between DEGs were identified in STRING and further network analyses highlighted 24 and 6 hub genes for normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. Moreover, four biologically meaningful modules including 251 genes were identified for normal vs. ACs. Biological network analyses indicated the involvement of hub genes in many vital pathways like JAK-STAT signaling pathway, interferon, Interleukins, and immune pathways in the normal vs. HAM/TSP group and Metabolism of RNA, Viral mRNA Translation, Human T cell leukemia virus 1 infection, and Cell cycle in the normal vs. ACs group. Moreover, three major genes including STAT1, TAP1, and PSMB8 were identified by network analysis. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P = 0.01 and P = 0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P = 0.04 and P = 0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P = 0.008 and P = 0.02, respectively). No significant difference was found among three groups in terms of the percentage of T helper and cytotoxic T lymphocytes (P = 0.55 and P = 0.12). CONCLUSIONS: High-throughput data integration disclosed novel hub genes involved in important pathways in virus infection and immune systems. The comprehensive studies are needed to improve our knowledge about the pathogenesis pathways and also biomarkers of complex diseases.

Mycobacterium tuberculosis Ag85b:hfcγ1 recombinant fusion protein as a selective receptor-dependent delivery system for antigen presentation.

Introducing an effective vaccine for tuberculosis (TB) is an urgent need. Mycobacterium tuberculosis (Mtb) Ag85 complex is suggested for making protective immunodominant antigens for design and development of novel TB vaccine. In the present study, a pDR2EF1-Fcγ1 vector has been used to make Ag85B:hFcγ1 recombinant fusion protein. Briefly, specific XbaI and NotI site incorporated primers were used to amplify Mtb-fbpB gene by PCR, TA-cloned and amplified in E.coli DH5α. The resulting vector then subcloned into the pDR2EF1.Fcγ1 vector and transferred to Chinese hamster ovary (CHO) cell line. DNA sequencing was performed to confirm that Ag85B:hFcγ1 construct is precise and in-frame. Then, Ag85B:hFcγ1 protein was produced by CHO expression system and recombinant protein was purified using HiTrap rProtein A Sepharose Fast Flow column. The presence of recombinant fusion protein confirmed by immunofluorescence (IFA) and Western blotting (WB). This fusion protein containing Fc fragment of human IgG1, apart from stability and adjuvanticity potential, could bind to FcRγI (CD64) on the surface of antigen-presenting cells (APCs) and induce cross-presentation in favour of host immune response and can be used as a potential candidate along with other subunit vaccines against Mtb.