HTLV-1 vaccination Landscape: Current developments and challenges.

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is distinguished for its correlation to myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). As well, HTLV-1 has been documented to have links with other inflammatory diseases, such as uveitis and dermatitis. According to the World Health Organization (WHO), the global distribution of HTLV-1 infection is estimated to extend between 5 and 10 million individuals. Recent efforts in HTLV-1 vaccine development primarily involve selecting viral components, such as antigens, from structural and non-structural proteins. These components are chosen to trigger a vigorous immune response from cytotoxic T lymphocytes (CTLs), helper T lymphocytes (HTLs), and B cells. Investigation into developing a vaccine against HTLV-1 is ongoing, and current surveys have explored several approaches, including viral vector vaccines, DNA vaccines, protein and peptide vaccines, dendritic cell-based vaccines, mRNA vaccines, and other platforms. Despite these investigations have shown promising results, challenges like the necessity for long-term protective immunity, addressing viral diversity, and managing potential side effects remain. It is critical to keep track of the progress made in HTLV-1 vaccination research to comprehend the development status and its possible impacts. The evolving nature of vaccine development underscores the importance of staying informed about advancements as we strive to combat HTLV-1-associated diseases through effective vaccination strategies. In this review, our goal is to provide an overview of the current status of HTLV-1 vaccination efforts, emphasizing the progress, challenges, and potential future directions in this vital area of research.

Effects of HTLV-1 on leukocyte trafficking and migration in ACs compared to healthy individuals.

Human T-lymphotropic virus type 1 (HTLV-1) is a RNA virus belonging to Retroviridae family and is associated with the development of various diseases, including adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Aside from HAM/TSP, HTLV-1 has been implicated in the development of several disorders that mimic auto-inflammation. T-cell migration is important topic in the context of HTLV-1 associated diseases progression. The primary objective of this case-control study was to assess the relationship between increased mRNA expression in virus migration following HTLV-1 infection. PBMCs from 20 asymptomatic patients and 20 healthy subjects were analyzed using real-time PCR to measure mRNA expression of LFA1, MLCK, RAC1, RAPL, ROCK1, VAV1 and CXCR4. Also, mRNA expression of Tax and HBZ were evaluated. Mean expression of Tax and HBZ in ACs (asymptomatic carriers) was 0.7218 and 0.6517 respectively. The results revealed a noteworthy upregulation of these genes involved in T-cell migration among ACs patients in comparison to healthy individuals. Considering the pivotal role of gene expression alterations associated with the progression into two major diseases (ATLL or HAM/TSP), analyzing the expression of these genes in the ACs group can offer probable potential diagnostic markers and aid in monitoring the condition of ACs.

Role of Interleukin-17 cytokine family in human T-cell lymphotropic virus type 1 (HTLV-1) infection and associated diseases.

BACKGROUND: Human T-lymphotropic virus (HTLV-1) is a neglected virus with worldwide distribution of over 10 million people and is the cause of two main associated diseases Adult T cell Leukemia-Lymphoma (ATLL), and HTLV-1-associated Myelopathy/Tropical Spastic paraparesis (HAM/TSP). The IL-17 cytokine family plays a crucial role in the host immunity against HTLV-1 and the development of associated disease. A systematic review was conducted to analyze all research reporting on the levels or expression of the IL-17 HTLV-1 infection and associated diseases. METHODS: The literature search was conducted in electronic databases including PubMed/Medline and Web of Sciences until January 31st, 2024, followed by the PRISMA guidelines. RESULTS: Our search revealed 20 eligible articles to be included in our study. The total number of cases studied was 1420, of which 386 were carriers without any symptoms, and were 176 ATLL and 237 HAM/TSP. The IL-17 cytokine family production or mRNA expression was higher in HAM/TSP patients but showed a trend toward reduction in the case of ATLL. CONCLUSIONS: Our results showed that while The IL-17 cytokine family plays a significant role in the immunopathogenesis of disease and clinical status of patients with inflammatory disorders such as HAM/TSP, IL-17 production is diminished and the RORC/IL-17 signaling pathway is downregulated during ATLL. Our data suggest that boosting the RORC/IL-17 signaling pathway in ATLL and using anti-IL-17 agents in HAM/TSP and other HTLV-related inflammatory conditions might benefit patients and improve their outcomes.

Leukemia-Related Signaling Pathways Among HTLV-1-Derived Adult T Cell Leukemia/Lymphoma and Asymptomatic Carriers in Comparison to Normal Group.

Human T cell lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma (ATLL), a fetal malignant infection. Recently, HTLV-1 new asymptomatic carriers (ACs) have frequently been reported among blood donors. Reaching the profound concept of HTLV-1-associated molecular pathogenesis could result in finding novel therapeutic strategies. The current study aimed to determine leukemia-related signaling regulation in ATLL. Thirty participants were evaluated in 3 groups, including 10 ATLL patients, 10 ACs, and 10 normal controls. Blood samples were isolated without any chemotherapy history from ATLL patients. Also, blood samples were recovered from ACs and normal individuals. White blood cells isolation was done on the collected blood samples. After this, RNA was extracted from the prepared samples and used for the cDNA synthesis. TAX and HTLV-1 basic leucine zipper factor as viral genes and cellular genes, including MKP-1, EVI-1, JNK-1, FOXO-1, AKT-1, DEPTOR, MTOR, and JUN, were investigated using real-time PCR. The mean age of ATLL patients was 53.2 ± 7.32 years, and 9 (90%) were male. The EVI-1 and FOXO-1 expression levels were significantly associated with ATLL patients compared with the internal control. However, the significant differences in expression of other genes in the remaining groups were not seen. Discovering viral and cellular signaling pathways that regulate HTLV-1 transformation is essential. A novel therapeutic strategy for ATLL-regulating cellular signaling pathways in vivo could be considered. Therefore, clinical trials using activators and inhibitors of related cellular signaling pathways for cell therapy of ATLL are recommended. It is recommended that more investigation be conducted on FOXO-1 and EVI-1 to target these genes and reveal the molecular pathogenesis of ATLL.

Alkalinization Using Sodium Bicarbonate for COVID-19 Treatment: A Systematic Review and Meta-Analysis.

BACKGROUND: A systematic review and meta-analysis have been conducted to evaluate the efficacy of alkalinization for COVID-19 patients based on current evidence to determine the impact of alkalinization on COVID-19 outcomes. METHODS: We searched MEDLINE (Pubmed), Web of Science, Cochrane Library, and Clinicaltrials.gov for studies evaluating the efficacy of alkalinization up to 30 April 2023. Based on the PRISMA 2020 statement criteria a systematic review and meta-analysis of studies were performed. RESULTS: The results of our meta-analysis showed a significant reduction in mortality rate in the alkalinization group compared to controls (RR 0.73, 95% CI: 0.56-0.95; I2 = 0%). However, our subgroup analysis showed no significant improvement in RCT-only studies (RR 0.78, 95% CI: 0.59-1.05; I2 = 0%), the recovery rate was significantly higher in the alkalinization group (RR 2.13, 95% CI: 1.39-3.26; I2 = 0%), duration of recovery also has improved in alkalinization group (SMD 0.76, 95% CI: 0.33-1.18; I2 = 0%). The results of our meta-analysis showed a significant reduction in the duration of hospitalization in the alkalinization group compared to controls with very low certainty of evidence (SMD -0.66, 95% CI: -0.97 to -0.35; I2 = 36%). CONCLUSION: With low certainty of evidence, alkalinization (by sodium bicarbonate) can be an efficient and safe adjuvant treatment for COVID-19 patients. Future randomized controlled trials are needed to strengthen the available evidence.

Higher expression of BRCA1, and CHUK and lower expression of NFKBIA, ESR1, PIK3R1, and PPARG in HAM/TSP compared to ATLL, a diverse pathological consequence.

BACKGROUND: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL) are both severe diseases caused by Human T-lymphotropic virus type 1 (HTLV-1) infection, while about 95% of infected cases remain asymptomatic. Genes that play a role in ATLL development are assumed to be dissimilar from the ones that are crucial factors for HAM/TSP occurrence. OBJECTIVE: The expression of six genes including BRCA1, CHUCK, ESR1, NFKBIA, PIK3R1, and PPARG were assessed in two groups of HAM/TSP and ATLL patients. Materials and Methods: cDNA was synthesized from purified RNA, and RT-qPCR was conducted to assess the expression of the genes in two groups. Any possible correlation among the genes' expression was also calculated. Results: BRCA1 and CHUCK expressions were higher in HAM/TSP patients in comparison with ATLL patients. However, ESR1, NFKBIA, PIK3R1, and PPARG are more expressed in ATLL cases than HAM/TSP. A significant positive correlation was observed between BRCA1 and NFKBIA in HAM/TSP group. In addition, a significant negative correlation between PIK3R1 and PPARG in HAM/TSP and between ESR1 and NFKBIA in the ATLL group was obtained. CONCLUSION: HAM/TSP or ATLL stem from a disturbance in the expression of diverse genes and these dissimilarities should be discovered to reach a better understanding of disease treatment as well as screening and assessing the asymptomatic carriers' condition for developing severe disease.

Possible role of intestinal fungal dysbiosis in dectin-1 and cytokines expression in patients with ulcerative colitis.

BACKGROUND: Dysregulation of cytokines and intestinal mycobiome has been surveyed in the progression of inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD). On the other hand, the intestinal fungal flora and its main receptor, Dectin-1, induce immune-derived cytokines. METHODS: Total 64 individuals comprising 32 patients with UC (case group) and 32 healthy subjects (HS group) were assessed. The type and prevalence of fecal yeast species were determined by deoxyribonucleic acid (DNA) sequencing through polymerase chain reaction (PCR) amplification using ITS4 and ITS5 primers. Furthermore, the ribonucleic acid (RNAs) of IL-4, IL-10, IL-17, IL-22 and IFN-γ were extracted. The expression of Dectin-1 gene was then measured in the excised tissue samples. RESULTS: A higher global fungal load in UC-affected patients (75%) was found in comparison with the HS group (25%), especially Candida albicans. Saccharomyces cerevisiae was significantly reduced in the fecal samples of UC-affected patients compared to HS (15.04% vs. 1.93% UC). The expression level of Dectin-1 was significantly elevated in patients with active UC (7.37 ± 0.81) than in patients with non-active UC (5.01 ± 77.25) and healthy controls (0.97 ± 0.24) (p < 0.05). The expression levels of IL-4, IL-10, especially both IL-17 and IL-22, were higher in the active UC group compared to the HS group (p = 0.0101, p = 0.0155, p < 0.0001, p < 0.0001, respectively). Similar expression level of IL-4, IL-10, IL-17, IL-22 (p > 0.999) and lower expression of interferongamma (IFN-γ) (p = 0.0021) were found in the non-active UC group compared to the HS group. A significant weak to moderate correlation was detected between Dectin-1 and IL-17 (r = 0.339, p = 0.019), as well as Dectin-1 and IL-22 (r = 0.373, p = 0.015). Furthermore, the expression levels of Dectin-1, IL-17 and IL-22 displayed significant associations with disease activity (p < 0.001, p = 0.029 and p = 0.003, respectively), regardless of the participant group. CONCLUSIONS: The current study revealed a possible role for intestinal fungi to promote colonic inflammation and increase UC activity through Dectin-1 stimulation. A positive correlation was detected between intestinal fungal richness with UC susceptibility and activity. IL-4 and IL-10 were associated with disease activity. Besides, the expression levels of Dectin-1, IL-17 and IL-22 were independently associated with disease activity.

Human T-cell lymphotropic virus type 1 (HTLV-1) grip on T-cells: investigating the viral tapestry of activation.

INTRODUCTION: Human T-cell Lymphotropic virus type 1 (HTLV-1) belongs to retroviridae which is connected to two major diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and Adult T-cell leukemia/lymphoma (ATLL). This study aims to investigate the mRNA expressions of key proteins correlated to T-cell activation in asymptomatic carriers (ACs) HTLV-1 infected patients, shedding light on early molecular events and T-cell activation following HTLV-1 infection. MATERIAL AND METHODS: The study involved 40 participants, including 20 ACs and 20 healthy subjects. Blood samples were collected, ELISA assessment for screening and confirmation with PCR for Trans-activating transcriptional regulatory protein (Tax) and HTLV-1 basic leucine zipper factor (HBZ) of the HTLV-1 were done. mRNA expressions of C-terminal Src kinase (CSK), Glycogen Synthase Kinase-3 Beta (GSK3ß), Mitogen-Activated Protein Kinase 14 (MAP3K14 or NIK), Phospholipase C Gamma-1 (PLCG1), Protein Tyrosine Phosphatase non-Receptor Type 6 (PTPN6) and Mitogen-Activated Protein Kinase Kinase Kinase-7 (SLP-76) and Mitogen-Activated Protein Kinase14 (MAP3K7 or TAK1) were assayed using RT-qPCR. Statistical analyses were performed using PRISM and SPSS software. RESULTS: While there were no significant upregulation in CSK and PTPN6 in ACs compared to healthy individuals, expression levels of GSK3ß, MAP3K14, PLCG1, SLP-76, and TAK1 were significantly higher in ACs compared to healthy subjects which directly contributes to T-cell activation in the HTLV-1 ACs. CONCLUSION: HTLV-1 infection induces differential mRNA expressions in key proteins associated with T-cell activation. mRNAs related to T-cell activation showed significant upregulation compared to PTPN6 and CSK which contributed to T-cell regulation. Understanding these early molecular events in ACs may provide potential markers for disease progression and identify therapeutic targets for controlling viral replication and mitigating associated diseases. The study contributes novel insights to the limited literature on T-cell activation and HTLV-1 pathogenesis.

Determination of molecular epidemiologic pattern of human T-lymphotropic virus type 1 (HTLV-1) in Alborz province, Iran.

Human T-cell lymphotropic virus type 1 (HTLV-1) is linked to two debilitating diseases, adult T-cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy tropical spastic paraparesis (HAM/TSP), which are prevalent in various parts of the world, including the Alborz province in Iran. Understanding the prevalence and evolutionary relationships of HTLV-1 infections in these endemic areas is of utmost importance. In the realm of phylogenetic studies, long terminal repeat (LTR) region of HTLV-1 stands out as highly conserved, yet more variable compared to other gene segments. Consequently, it is the primary focus for phylogenetic analyses. Additionally, trans-activator of transcription (Tax), an oncoprotein, holds a pivotal role in the regulation of gene expression. This cross-sectional study delved into the phylogenetic analysis of HTLV-1 among individuals in Alborz province of Iran. To confirm infection, we amplified partial sequence LTR (PLTR) and HTLV-1 bZIP factor (PHBZ). For phylogenetic analysis, we sequenced the full sequence LTR (FLTR) and full Tax sequence (FTax). The FLTR and FTax sequences underwent analysis using BioEdit, and phylogenetic trees were constructed using MEGA-X software. Out of the roughly 15,000 annual blood donors in Alborz, 19 samples tested positive for HTLV-1, indicating a 0.13% HTLV-1 positivity rate among blood donors. Furthermore, the HTLV-1 virus prevalent in the Alborz province belongs to subtype A (cosmopolitan) subgroup A. The findings revealed that while mutations were observed in both the LTR and Tax genes, they were not significant enough to bring about fundamental alterations. Despite positive selection detected in three Alborz isolates, it has not led to mutations affecting Tax function and virulence.

Unraveling the dynamic mechanisms of natural killer cells in viral infections: insights and implications.

Viruses pose a constant threat to human well-being, necessitating the immune system to develop robust defenses. Natural killer (NK) cells, which play a crucial role in the immune system, have become recognized as vital participants in protecting the body against viral infections. These remarkable innate immune cells possess the unique ability to directly recognize and eliminate infected cells, thereby contributing to the early control and containment of viral pathogens. However, recent research has uncovered an intriguing phenomenon: the alteration of NK cells during viral infections. In addition to their well-established role in antiviral defense, NK cells undergo dynamic changes in their phenotype, function, and regulatory mechanisms upon encountering viral pathogens. These alterations can significantly impact the effectiveness of NK cell responses during viral infections. This review explores the multifaceted role of NK cells in antiviral immunity, highlighting their conventional effector functions as well as the emerging concept of NK cell alteration in the context of viral infections. Understanding the intricate interplay between NK cells and viral infections is crucial for advancing our knowledge of antiviral immune responses and could offer valuable information for the creation of innovative therapeutic approaches to combat viral diseases.