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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Human T lymphotropic virus type 1 (HTLV‐1) infection with high prevalence in the north‐east of Iran, particularly in Mashhad, can lead to adult T‐cell leukemia (ATL) and HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a variety of autoimmune diseases. The aim of the study was to examine the presence of autoimmune markers in HTLV carries. Methods: Serum samples were obtained from blood donors in Mashhad, northeastern Iran. One hundred and five HTLV‐1 positive (cases) and 104 age‐ and sex‐matched HTLV‐1 negative donors (controls) were assessed for presence of serum autoimmune markers by enzyme‐linked immunosorbent assay. Results: The mean ages of cases and controls were 40.8 ± 9.4 and 41.5 ± 9.3 years, respectively (P = 0.5). In the case group, 81.9% and in the control group 83.7% were male (P = 0.74). The frequency of positive antinuclear antibodies and anticyclic citrullinated peptide antibodies in the serum of the two groups were not significantly different (P = 0.68 and P = 0.62, respectively). Only one antineutrophil cytoplasmic antibody‐positive case (1%) was observed in the group and no anti‐phospholipid immunoglobulin G positivity was observed. The frequency of rheumatoid factor (RF) was greater in case group than in the control group, although the difference was not significant (P = 0.08). The amount of RF in all 12 RF positive sera were higher than normal levels (33–37 IU/mL). Conclusion: Because we failed to detect any significant relation between serum autoimmune markers and HTLV‐1 infection, and because of the relatively low prevalence of autoimmune diseases, it could be concluded that healthy HTLV‐1 carriers do not produce rheumatologic‐related auto‐antibodies more than the healthy population. [ABSTRACT FROM AUTHOR]

The study of tumor viruses paves the way for understanding the mechanisms of virus pathogenesis, including those involved in establishing infection and dissemination in the host tumor affecting immune-compromised patients. The processes ranging from viral infection to progressing malignancy are slow and usually insufficient for establishment of transformed cells that develop cancer in only a minority of infected subjects. Therefore, viral infection is usually not the only cause of cancer, and further environmental and host factors, may be implicated. HTLV-I, in particular, is considered as an oncovirus cause of lymphoproliferative disease such as adult T cell leukemia/lymphoma (ATL) and disturbs the immune responses which results in HTLV-I associated meylopathy/tropical spastic parapresis (HAM/TSP). HTLV-I infection causes ATL in a small proportion of infected subjects (2-5%) following a prolonged incubation period (15-30 years) despite a strong adaptive immune response against the virus. Overall, these conditions offer a prospect to study the molecular basis of tumorgenicity in mammalian cells. In this review, the oncogencity of HTLV-I is being considered as an oncovirus in context of ATL. [ABSTRACT FROM AUTHOR]

• Human papilloma virus (HPV) prevalence, genotypes and phylogenetics was investigated in northeast Iran. • Eleven new HPV sequences were identified. • Conservative populations were less affected by HPV infection. • Increased knowledge of HPV and establishment of diagnostic facilities and vaccination programs is needed. Human papillomaviruses (HPV) are the main etiology of invasive cervical cancer. Together HPV and viral hepatitis account for the cause of 25% of cancers in developing countries. To evaluate the association between population movements and the spread of HPV, this study looked at prevalence, genotypes, and phylogenetic assessment of HPV in Great Khorasan, a pilgrimage-tourism province in northeast Iran. From March 2013 to July 2018, 567 samples were collected from three groups in Khorasan: Razavi and North Khorasan provinces (highly mobile population); South Khorasan province (conservative and desert); and diverse group (tourists). HPV prevalence was 48.4% in Razavi and North Khorasan (first group); 19.9% in South Khorasan (second group); and 33.6% in the diverse group. The four most common HPV genotypes were HPV-6, 11, 51 and 16, in the first group; HPV-6, 11, 16 and 58 in the second group; and HPV-6, 11, 16 and 53/89 in the diverse group. The most frequent genotypes that are known as high risk for cervical cancer were HPV-51 in the first group, HPV-16 in the second group and the diverse group. Among low-risk genotypes, HPV-6, and HPV-11 were more frequent in all groups. DNA sequencing and phylogenetic analysis of 20 HPV-positive samples showed that the distributions of the HPV genotypes were HPV-6 (50%), 11 (10%), 67 (5%), 16 (15%), 31 (10%), 54 (5%), and 89 (5%). The findings show that areas associated with population movement should be frequently monitored for infectious diseases, while conservative and less populated areas have less risk for virus spread and endemicity. Health authorities should focus more on the establishment of HPV diagnostic facilities, screening, vaccination, and enhancement of public knowledge in these regions. [ABSTRACT FROM AUTHOR]

Objective(s): HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the most common neurological manifestation of HTLV-I. The northeast of Iran is an endemic area for this virus. Host genetic and viral factors play important roles in developing HAM/TSP. The aim of this study was to evaluate the proviral load, and clinical features of HAM/TSP among Iranian to compare with other endemic parts of the world. Materials and Methods: In this systematic retrospective study, HTLV-I proviral load of 102 Iranian patients with HAM/TS,P and 34 healthy carriers in peripheral blood mononuclear cells (PBMCs) were measured using real-time quantitative PCR assay. The diagnosis of HAM/TSP was made in accordance with the World Health Organization criteria. Results: The mean HTLV-I proviral load of Iranian HAM/TSP patients (626 ± 53.031copies/104 PBMCs) was lower than other populations (in Japanese about 800 copies/104 PBMCs and in Brazilians 912.5 ± 778.6 copies/104 PBMCs). In contrast, the mean HTLV-I proviral load amongst Iranian healthy carriers (193 ± 44.375 copies/104 PBMCs) was higher than that of Japanese healthy carriers (about 140 copies/104 PBMCs), and lower than Brazilians (240.5 ± 452.8 copies/104 PBMCs according to the literatures). The most common HAM/TSP neurological symptoms among Iranian, Japanese, and Brazilian populations were gait disturbance, urinary disturbance, paresthesias, weakness, constipation, and lower back pain. The HTLV-I proviral load in HAM/TSP patients and healthy carriers was not significantly associated with age and gender. Conclusion: Differences in HTLV-I proviral load and consequently clinical manifestations among Iranian and other endemic populations might be due the differences in host genetic background and environmental conditions of these populations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. • The expression of IFN-λ as an anti-viral agent was increased in ICB patients. • T-bet , the transcription factor for Th1, was up-regulated in ICB patients. • CREB , as T-cells regulating factor and macrophage functions, is up-regulated in ICBs. • Notably, the upregulation of these factors puts pressure on HBV activities in ICBs. • Surprisingly, the HBx regulatory factor was detected only in one ICB patient. [ABSTRACT FROM AUTHOR]

• ATLL malignancy and EBL oncogenesis pathways were investigated. • The RNA-seq, system biology analysis and gene expression assays were compared. • BLV-AS-1–2 in EBL and HTLV-1- HBZ have pivotal roles in the ATLL progression. • HTLV-1-PVL, Tax, and HBZ, the immunological and host-cell factors were evaluated. • HTLV-1-HBZ, the host PI3K/Akt pathway, BCAs, and RAD51 are influential targets. The outcome of successful infection, including human T -cell leukemia virus type 1 (HTLV-1), is determined by the interactions between the host and the infectious agent. Ten years of work on HTLV-1-associated diseases in an endemic region of Iran have been critically compared in the present study. The outstanding findings of RNA-seq, system biology analysis, and gene expression measurements on adult T -cell leukemia/lymphoma (ATLL) and enzootic bovine leukosis (EBL) in our lab encouraged us to investigate the significant role of oncogenes in the ATLL malignancy. Most studies assessed such interactions by the proviral load (PVL), Tax, and HBZ regulatory proteins in HTLV-1 and the host's immunological and cell cycle factors. The current study is a comprehensive comparing view of our previously published and unpublished results investigating the HTLV-1-host interactions leading to the transformation of the infected cell. The main focus has been on the essential proteins implicated in the virus dissemination, cell survival, and proliferation of infected cells toward leukemia development and progression. Similar to its homolog BLV-AS-1–2 in EBL, the HTLV-1- HBZ is a pivotal factor in the maintenance and progression of the ATLL. In addition, the inappropriate activities of the PI3K/Akt pathway, BRCAs, and RAD51 in the DNA repair system, which are orchestrating many other immortalization pathways, might be the central factors in the manifestation of ATLL. HTLV-1- HBZ and the host PI3K/Akt pathway, BCAs , and RAD51 could be suggested as influential targets for the prognosis and proper therapy of ATLL. [ABSTRACT FROM AUTHOR]