Human T-cell Lymphotropic Virus Infection Research Articles

B-080 Analytical Performance of ESPLINE HTLV-I/II

Abstract Background The human T-cell lymphotropic virus (HTLV) infects a type of white blood cell called T-cell or T-lymphocyte. There are two types of HTLV, HTLV-I and HTLV-II, which are closely related to human C retroviruses. HTLV-I is endemic in the Caribbean, Japan, South America, and parts of Africa. HTLV-I has been recognized as a cause of adult T-cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-II is found among Africa and the Americas, and injecting drug users in many cities of Western Europe and North America. Currently, an effective vaccine against HTLV is not available, and clinical treatment is limited. The diagnosis and identification of patients are very important for controlling the spread of HTLV infection. There are HTLV-infected lymphocytes in the peripheral blood of patients, but little virus in the serum or plasma can be detected. Therefore, screening tests for HTLV that generally detect antibodies using reagents need dedicated instruments. We have developed an anti-HTLV-I/II reagent ( ESPLINE HTLV-I/II) based on the immunochromatography principal using an enzyme immunometric assay that can easily detect both anti-HTLV-I and anti-HTLV-II antibodies in serum and plasma. This report evaluates its efficacy. Methods This reagent has a test line coated with a recombinant protein and peptides derived from three env gene proteins (HTLV-I gp21, HTLV-I gp46, and HTLV-II gp46) to detect anti-HTLV-I/II antibodies. The antibodies in the sample bind to antigens labelled with alkaline phosphatase (ALP), and then immunocomplexes are formed. These complexes are captured by the antigens on the test line, and the blue line is detected by ALP enzymatic reaction with a colorimetric substrate. It only takes 15 minutes to obtain the results without any instruments. To evaluate the fundamental performance, we tested specificity, limit of detection, and method comparison with Lumipulse HTLV-I/II, Lumipulse Presto HTLV-I/II, and Serodia HTLV-I, following the CLSI protocol. Commercially available serum and/or plasma were used for most evaluations. Results Regarding specificity, 1014 anti-HTLV-I/II negative serum samples, which were confirmed by highly sensitive CLEIA Lumipulse Presto HTLV-I/II, were tested by ESPLINE HTLV-I/II. Then, all 1014 samples were shown as nonreactive, demonstrating a specificity of 100.0%. Regarding the limit of detection, by the analysis of serial dilution from 2 positive plasma specimens, ESPLINE HTLV-I/II assay showed high sensitivity compared to conventional Serodia HTLV-I. Regarding the method comparison, 57 anti-HTLV-I and 30 anti-HTLV-II positive plasma samples from different individuals were tested. All samples showed positive results with ELPLINE HTLV-I/II, Lumipulse Presto HTLV-I/II, Lumipulse G HTLV-I/II, and conventional Particle Agglutination Serodia HTLV-I. Conclusion The novel anti-HTLV-I and anti-HTLV-II antibodies assay, ESPLINE HTLV-I/II, showed higher sensitivity than Particle Agglutination Serodia HTLV-I and had good concordance with highly sensitive CLEIA Lumipulse Presto HTLV-I/II and Lumipulse G HTLV-I/II. The ESPLINE system can be used easily to complete an assay in 15 min. This procedure is considered useful in situations such as on-site tests at health centers, screening tests at medical institutions with a small number of specimens, and other emergency tests.

Adult t-cell leukemia/lymphoma: case report in southern Brazil

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive type of non-Hodgkin's lymphoma that can be primary of the skin or secondary, caused by Human T-cell lymphotropic virus (HTLV-1) infection. The prevalence of HTLV-1 infection is high in Brazil, however reports of ATLL are rare, possibly underdiagnosed and underreported. This paper presents a case report of a patient coming from the south of Brazil, a region of the country with few cited cases of this comorbidity. It shows the importance of disclosing data on infection by the virus, so that public policies for prevention can be carried out, as well as the presentation of cases that develop ATLL.

Clinical Characteristics and Outcomes of Infection with Human T-Cell Lymphotropic Virus (HTLV) in a Non-Endemic Area: A Single Institution Study

Introduction: The first human oncogenic retrovirus discovered, human T cell lymphotropic virus (HTLV) remains poorly understood. Etiologically associated with adult T-cell leukemia (ATL), HTLV type 1 (HTLV-1) causes lifelong latent infection in CD4+ T cells and is estimated to affect between 5 to 20 million individuals globally. Despite being closely related, HTLV-2 infection has not been casually linked to clinical disease. In recent years, there has been an increased incidence of HTLV in the United States, however, affected patients are often under- and mis-diagnosed. While great strides have been made in understanding the virology, epidemiology, and clinical course of HTLV-1 and HTLV-2 infection, much of our current knowledge of HTLV and HTLV-related diseases is based on research in endemic areas, particularly Japan. We sought to characterize the epidemiology, clinical features, comorbidities, and survival of HTLV-1- or HTLV-2-positive individuals identified in a non-endemic area, using patient information from our academic institution. Methods: Our study was a single institution, retrospective case-control analysis of HTLV-1 or HTLV-2 patients between 1998 and 2020. We utilized two HTLV-negative controls, matched for age, sex, and race, for each one HTLV-positive case. Hematologic, neurologic, and rheumatologic covariates, including viral co-infection, opportunistic illnesses, malignancy, and clinical characteristics, were evaluated as variables affecting overall survival (OS). Results: We identified 38 cases of HTLV infection, of whom 23 were HTLV-1 and 15 were HTLV-2 positive. Median follow up was 39.7 months and median OS was 67.2 months for HTLV-seropositive patients, compared to 49.6 months and 131.2 months, respectively, for HTLV-seronegative patients. HTLV-1 positive patients had lower median OS compared to HTLV-2 patients (47.7 months vs. 77.36 months). During follow-up, 21 of 38 HTLV-seropositive patients died, compared to 33 of 76 HTLV-seronegative patients who died. Underlying reasons for HTLV testing were grouped into eight mutually exclusive categories: transplant evaluation, neurologic deficit(s), hematologic disorder, dermatologic, gastrointestinal, lymphadenopathy, infection, and other/unknown. Notably, the majority (53.9%) of patients in our control group received HTLV testing for transplant evaluation testing, compared to 23.7% of HTLV-seropositive patients. In evaluation of co-morbidities associated with HTLV, hepatitis C seropositivity was higher in HTLV-seropositive patients compared to controls (OR 16.8, 95% CI = 3.4 - 81.8, p < 0.001). There were no cases of HIV infection in our study. In Kaplan Meier analysis, hepatitis C and HTLV co-infection resulted in decreased 1-year and 3-year OS, compared to no infection, hepatitis C infection alone, or HTLV infection alone (Figure 1). Similarly, patients with any cancer diagnosis and HTLV infection had worse 1-year OS compared to patients with cancer or HTLV alone. There was no significance in 1-year OS with other risk factors, including CMV/HTLV co-infection or blood stream bacterial/HTLV co-infection. In univariate analysis, the hazard for 1-year all-cause mortality was increased among patients with HTLV-seropositivity (unadjusted HR 3.4, 95% CI 1.4- 8.2, P = 0.006), ATL (unadjusted HR 4.8, 95% CI 1.8 - 13.3, P = 0.08), AML (unadjusted HR 4.3, 95% CI 1.6-11.9, P = 0.01), and hepatitis C infection (unadjusted HR 3.2, 95% CI 1.2-8.5, P = 0.03) (Table 1). When corrected, multivariate analysis showed that HTLV seropositivity was no longer associated with 1-year all-cause mortality; however association with AML (adjusted HR 10.0, 95% CI 2.8-35.2, P = 0.0003) and hepatitis C infection (adjusted HR 7.0, 95% CI 1.5 - 32.0, P = 0.01) remained significant. Conclusions: HTLV-seropositivity was not associated with increased 1-year mortality in multivariate analysis. Our study is limited by our small patient sample size, as well as the biased patient control population due to HTLV testing. These studies warrant continued evaluation of clinical characteristics and outcomes of HTLV infection in non-endemic regions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Human T-Cell Lymphotropic Virus (HTLV-1) Infection in the Democratic Republic of the Congo: A Review of a Forgotten Epidemic

Human T-Cell Lymphotropic Virus (HTLV-1) Infection in the Democratic Republic of the Congo: A Review of a Forgotten Epidemic

Screening for Human T-Cell Lymphotropic Virus (HTLV) in Pregnant Women in the Peruvian Amazon and Systematic Review with Meta-Analysis of HTLV Infection in Peru.

Background. Human T-cell lymphotropic virus type 1 (HTLV-1) is responsible for tropical spastic paraparesis and HTLV-1-associated leukemia/lymphoma. The infection is endemic in some areas of Peru, but its prevalence in the Peruvian Amazon is not well established. We aimed to assess the seroprevalence of HTLV-1 infection in pregnant women in the Peruvian Amazon. Moreover, we performed a systematic literature review and meta-analysis of the seroprevalence of HTLV infection in Peru. (2) Methods. This is a prospective cross-sectional study involving pregnant women attending health centers in the city of Iquitos, Peru, in May and June 2019. The presence of antibodies against HTLV-1 was assessed using ELISA (HTLV I + II ELISA recombinant v.4.0, Wiener lab, Rosario, Argentina). Positive cases were confirmed by Western Blot and HTLV-1 proviral load. (3) Results. The study included 300 pregnant women with a mean age of 26 years (standard deviation [SD] 6.4). Five patients were diagnosed with HTLV-1 infection (prevalence 1.7%, 95% confidence interval (CI) 0.7% to 3.8%). Pregnant women with HTLV-1 infection were discretely younger (mean age 22.6 [SD 22.6] vs. 26.8 [SD 6.3]; p = 0.128). None of the five women had been transfused, and all were asymptomatic. Two (40%) also had a positive serology for Strongyloides, but larvae were not detected in any of the parasitological stool studies. The systematic review component identified 40 studies, which showed that the prevalence of HTLV infection in the general population was 2.9% (95% CI 1.2% to 5.3%) and in women of childbearing age, 2.5% (95% CI 1.2% to 4.0%). (4) Conclusion. The prevalence of HTLV-1 in the Peruvian Amazon basin is about 1.7%, indicating an endemic presence. Screening for HTLV-1 in prenatal care is warranted.

Prevalence and evolutionary analyses of human T-cell lymphotropic virus in Guangdong province, China: Transcontinental and Japanese subtype lineages dominate the prevalence.

To systematically characterize the prevalence and evolution of human T-cell lymphotropic virus (HTLV) infection among voluntary blood donors (BDs) in Guangdong province, China. A three-year survey for HTLV epidemiology among BDs was performed in Guangdong during 2016-2018. Anti-HTLV-1/2 was screened by ELISA and ECLIA, and subsequently confirmed by western blot (WB) and nucleic acid testing (NAT). The prevalence of HTLV in donors from different cities was calculated. The identified HTLV-positive cases were phylogenetically genotyped and analyzed in a Bayesian phylogenetic framework. Among 3,262,271 BDs, 59 were confirmed positive for HTLV-1 (1.81 per 100,000) and no HTLV-2 infection was found. The prevalence of HTLV-1 varied significantly among 21 cities in Guangdong province, China. The highest prevalence was found in donors from Shanwei (13.94 per 100,000), which is a coastal city in eastern Guangdong. Viral genomic sequences genotyped from 55 HTLV-1 carriers showed that 39 were transcontinental subtype and 16 were Japanese subtype. Specially, 13 out of 39 transcontinental subtype sequences were characterized with L55P mutation and 21 out of 55 sequences were characterized with L19F mutation in viral gp46 protein. The L55P mutation seemed be specific to eastern Asia since it only presented in the sequences from Japan, mainland China, and Taiwan. Phylogenetic analysis of gp46 gene shows that HTLV-1a may have been introduced to Guangdong through four different introduction events and formed major transmission clusters: clades I(13,602 years ago), II(16, 010 years ago), III(15,639 years ago) and IV(16,517 years ago). In general, Guangdong is considered to be a low-prevalence region for HTLV-1 infection, but the prevalence is significantly higher in Shanwei city. Transcontinental and Japanese subtype lineages dominate the prevalence in Guangdong. In terms of blood safety, HTLV antibody screening for first-time blood donors can effectively reduce the risk of HTLV transmission.

Brazilian Protocol for Sexually Transmitted Infections 2020: human T-cell lymphotropic virus (HTLV) infection.

This article addresses the Human T-lymphotropic virus (HTLV). This subject comprises the Clinical Protocol and Therapeutic Guidelines for Comprehensive Care for People with Sexually Transmitted Infections, published by the Brazilian Ministry of Health. HTLV-1/2 infection is a public health problem globally, and Brazil has the largest number of individuals living with the virus. HTLV-1 causes several clinical manifestations of neoplasm (adult T-cell leukemia/lymphoma) and inflammatory nature, such as HTLV-1-associated myelopathy and other manifestations such as uveitis, arthritis, and infective dermatitis. These pathologies have high morbidity and mortality and negatively impact the quality of life of infected individuals. This review includes relevant information for health authorities professionals regarding viral transmission, diagnosis, treatment, and monitoring of individuals living with HTLV-1 and 2 in Brazil.

Dual intestinal parasitosis unmasked by treatment for gastrointestinal sarcoidosis

The symptoms and complications of intestinal parasitosis can occur with long-term corticosteroid therapy. We highlight the case of a young man who developed chronic gastrointestinal (GI) symptoms of diarrhea, crampy abdominal pain, and vomiting while on treatment for multisystemic sarcoidosis with corticosteroids. His symptoms were initially thought to be related to the gastrointestinal manifestations of sarcoidosis, but further evaluation revealed a combined case of intestinal strongyloidiasis and giardiasis as well as previously undiagnosed human T-cell lymphotropic virus (HTLV -1) infection. This distinctive case of dual intestinal parasitosis highlights the need for clinicians to maintain a high level of awareness to screen for intestinal parasites, particularly Strongyloides when prescribing corticosteroids in the long term given the potential risk of hyperinfection in the setting of immunosuppression..

Molecular Epidemiology of HIV-1 and HTLV-1/2 Among Female Sex Workers in Four Cities in the State of Para, Northern Brazil.

Female sex workers (FSWs) represent a key population for the acquisition of sexually transmitted infections (STI) due to their social vulnerability and the risks associated with their occupation. This study was conducted to describe the sociodemographic characteristics and sexual behavior among FSWs in cities in northern Brazil, to determine the prevalence of human immunodeficiency virus 1 (HIV-1) and human T-cell lymphotropic virus (HTLV-1/2) infections and to identify the circulating subtypes of these agents in this key population. A cross-sectional study using the Time Location Sampling (TLS) method was conducted among 339 FSWs in cities in the state of Pará from 2005 to 2006. Serological and molecular tests were performed to identify infections and viral subtypes, and bivariate and multivariate analyses were conducted to identify risk factors. Most FSWs were young, single, less educated and had at least one child. The prevalence of antibodies against HIV-1 and HTLV-1 was 2.3 and 1.7%, respectively. HIV-1 subtypes B (87.5%) and F1 (12.5%) were identified among FSWs, as were Cosmopolitan subtype (1a) and Transcontinental subgroup (A). Unprotected sex and illicit drug use were associated with HIV-1 and HTLV-1 infections using bivariate and multivariate analyses, and age ≥27 years was associated only with HIV. The important information highlighted here clearly indicates that the lack of actions to control and prevent pathogens in FSWs and the lack of strategies for health promotion in key populations can further aggravate the epidemiological scenario of viral infections in remote areas with low human development indices. Neglecting these facts may be causing the spread of these two viruses and their respective subtypes in the general population of northern Brazil.

Impact of Human T-Cell Lymphotropic Virus Infection on Survival Following Stem Cell Transplantation

Human T-Cell Lymphotropic Virus (HTLV) Types 1 or 2 are delta retroviruses that may lead to complications including adult T-cell leukemia-lymphoma (ATLL) and HTLV-1-associated myelopathy (HAM). There is concern that immunosuppression may result in progression from an asymptomatic carrier state to ATLL or HAM. Data on the safety of stem cell transplantation (SCT) in patients with HTLV-1/2 infection are lacking. The Center for International Blood and Marrow Transplant Research (CIBMTR) was queried for all patients who tested positive for HTLV infection in the pre-transplantation workup and underwent either autologous SCT (AutoSCT) or allogeneic SCT (AlloSCT) between 2008-2017. The primary outcome was overall survival up to four years post-SCT, assessed using the Kaplan-Meier statistic. All analyses were univariate and did not adjust for differences in disease, disease stage or patients characteristics. In those who underwent AutoSCT, 54 (0.5%) patients were HTLV-positive and 9,837 were HTLV-negative. In those who underwent AlloSCT, 126 (0.7%) patients were HTLV-positive and 18,084 were HTLV-negative. In the HTLV-negative group, a larger proportion underwent AlloSCT for acute myeloid leukemia in the HTLV-negative group, while Non-Hodgkin lymphoma/other leukemia was more common in the HTLV-positive group (P&amp;lt;0.001). Additional patient demographics are listed in Table 1. No difference in overall survival (p=0.661) or non-relapse mortality (p=0.522) was noted following AutoSCT based on HTLV status. Following AlloSCT, univariate analysis showed the HTLV-positive patients had a statistically significant lower overall survival (Figure 1; p=0.013) and higher non-relapse mortality at year four (Figure 2; p=0.023). In conclusion, survival after AutoSCT seems unaffected by HTLV status. While the underlying indications for AlloSCT differed in HTLV-infected patients, decreased overall survival and increased non-relapse mortality were seen in HTLV-positive patients. Reasons for increased non-relapse mortality may include increased infectious complications or graft-versus-host disease. Further studies are needed to understand the relative contributions of these factors. Disclosures Janakiram: Takeda, Fate, Nektar: Research Funding. Sloan:Stemline: Consultancy; Abbvie: Consultancy.

The Frequency and Risk Factors of Human T-cell Lymphotropic Virus Type I among Blood Donors in Khorasan-e Razavi, Iran, from 2002 to 2013.

Introduction:Human T-cell lymphotropic virus (HTLV-I) is the causative agent for adult T-cell lymphoma/leukemia (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis. The virus is endemic in the parts of Iran. This study is conducted to determine the trends in the frequency of HTLV-I in Mashhad, a city in Khorasan-e Razavi province, Iran, over 11 years.Materials and Methods:Blood bank records of blood donors positive for HTLV-I were collected from different blood banks across Mashhad between 2002 and 2013. Obtained data were first entered into paper versions and then were analyzed by SPSS version 11.5. HTLV-I antibody was firstly measured by enzyme-linked immunosorbent assay (ELISA) method and later confirmed by the Western Blot (WB).Results:During the study period, 983,000 donors were examined by ELISA and WB, among whom 2921 cases (0.297%) were positive HTLV-I carriers. The highest and lowest frequency of carriers was 0.451% and 0.098%, respectively. The most significant factor was related to marital status (85.2%) and the smallest significant factor was associated with the history of acupuncture (0.3%) according to the different risk factors.Conclusion:The frequency of HTLV-I carriers among blood donors was significantly decreased in this period. Screening of blood donors for HTLV-I infection played a significant role in this reduction.

Pooling of sera for human T-cell lymphotropic virus (HTLV) screening in a time of increasing health care expenditure and limited resources.

ABSTRACTIdentifying the true prevalence of human T-cell lymphotropic virus, mostly type 1 (HTLV-1), and the number of patients with HTLV-1-associated diseases, in addition to introducing HTLV-1/2 serology during the prenatal of pregnant women and in individuals infected with other viruses that share transmission routes with HTLV-1, are actions that could help to recognize the importance of this virus by WHO and national health organizations, and to control its transmission/dissemination. As Brazil is endemic to HTLV and there is an increase in health care expenditure, but resources are limited, any strategy that could reduce the cost of HTLV screening is needed and welcomed. This study aimed to determine whether the strategy of pooling sera for HTLV antibody determination is feasible and reduces the costs. Two enzyme immunoassays (EIA Murex HTLV-I+II, Diasorin, UK, and Gold ELISA HTLV-1+2, REM Ind. Com. Ltda., SP, Brazil), and serum samples that resulted in different levels of HTLV-1/2 antibodies by EIA and of which a volume allowed assay validation were employed for analysis. The diagnostic sensitivity and specificity and Cohen’s Kappa value, as well as the accuracy and precision were analyzed. After validating the five-sample pool using the EIA Murex (Cohen’s Kappa = 1.0), the technique was employed for individual cost comparison in 2,625 serum samples from populations at risk of HTLV infections (HBV, HCV, and HIV-infected individuals). The results from individual and pooled samples confirmed the diagnostic sensitivity (100%) and specificity (100%) of the pooling and a cost minimization varying from 60.7% to 73.6%. In conclusion, the results of this study suggest the use of pooling sera in sero-epidemiological surveillance studies and possibly in prenatal care screening programs in Brazil.

Line Immunoassay for Confirmation and Discrimination of Human T-Cell Lymphotropic Virus Infections in Inconclusive Western Blot Serum Samples from Brazil.

Difficulties in confirming and discriminating human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 infections by serological Western blot (WB) assays (HTLV Blot 2.4; MP Biomedicals) have been reported in Brazil, mainly in HIV/AIDS patients, with a large number of WB-indeterminate and WB-positive but HTLV-untypeable results. Nonetheless, a line immunoassay (LIA) (INNO-LIA HTLV-I/II; Fujirebio) provided enhanced specificity and sensitivity for confirming HTLV-1/2 infections. To add information concerning the improved ability of the LIA in relation to WB when applied to samples of individuals from different risk groups from Brazil, we performed the present study. Three groups were analyzed: group 1 (G1), with 62 samples from HIV/AIDS patients from São Paulo, SP (48 WB indeterminate and 14 HTLV untypeable); group 2 (G2), with 24 samples from patients with hepatitis B or hepatitis C from São Paulo (21 WB indeterminate and 3 HTLV untypeable; 17 HIV seropositive); and group 3 (G3), with 25 samples from an HTLV outpatient clinic in Salvador, Bahia (16 WB indeterminate and 9 HTLV untypeable; all HIV seronegative). Overall, the LIA confirmed HTLV-1/2 infection (HTLV-1, HTLV-2, or HTLV) in 66.1% (G1), 83.3% (G2), and 76.0% (G3) of samples. Interestingly, the majority of WB-indeterminate results were confirmed by the LIA as being HTLV-2 positive in G1 and G2 but not in G3, in which the samples were defined as being HTLV-1 or HTLV positive. These results agree with the virus types that circulate in such patients of different regions in Brazil and emphasize that the LIA is the best serological test for confirming HTLV-1 and HTLV-2 infections, independently of being applied in HTLV-monoinfected or HTLV-coinfected individuals.

System Bioinformatic Approach Through Molecular Docking, Network Pharmacology and Microarray Data Analysis to Determine the Molecular Mechanism Underlying the Effects of Rehmanniae Radix Praeparata on Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Rehmanniae Radix Praeparata (RRP) is a popular medicinal herb widely used in traditional Chinese medicine (TCM) to treat CVDs. However, the development of this novel therapeutic product has been stagnant, and its molecular mechanism of action remains unclear. This study aims to explore the effective ingredients of RRP against CVDs, especially atherosclerosis (AS). Using the AutoDock Vina software, the RRP's ingredients were docked with the targets which can be collected by RCSB and UniProt. Then the screened ingredients and targets could be used to dispose the pathways by the Kyoto Encyclopedia of Genes and Genomes (KEGG). We used GEO, GCBI and DAVID databases to analyze the microarray data of AS which could be used to verify the results of molecular docking, all of which could show the molecular mechanism of RRP on CVDs. We also constructed a compound-target interaction network of CVD with 85 nodes and 272 edges on the basis of molecular docking analysis through Cytoscape. The network showed that forsythiaside, acteoside and stigmasterol are the most important compounds and 2HRR (ACAT (Acyl-CoA cholesterol acyl transferase) protein), 4ATB (MMP13) and 1JBQ (cystathionine beta-synthase) are the most valuable targets in the action of RRP against CVD. We also examined the biological functions involved in the biological process, molecular function and cellular components. In accordance with the analysis of GSE6054 microarray data of AS disease, the 20 most specifically expressed genes (differentially expressed genes [DEGs]) and the top 10 pathways of DEGs were discovered. Five key pathways, including non-alcoholic fatty liver disease (NAFLD), pathways in cancer and PI3K-Akt signalling pathway were also explored. Amongst these pathways, the top three were the pathways in cancer, MAPK signalling pathway and human T-cell lymphotropic virus infection. The pathways in cancer and PI3K-Akt signalling pathway were found simultaneously in the pathway analysis for CVD on RRP and for AS on microarray data. This study provided a new potential herbal medicine against CVD and has increased the understanding on the molecular mechanisms of RRPmediated protection against CVD, especially AS.

Vitamin D and HTLV Infection: A Systematic Review

Background:Vitamin D has been associated with the pathogenesis of infectious diseases.Objective:To perform a systematic review on the association of vitamin D and outcomes of HTLV (Human T-cell lymphotropic virus) infection.Methods:We searched PubMed, LILACs, Scielo, Embase and Cochrane Library for studies addressing vitamin D and HTLV infection. We included studies published in English since 1980. Studies associated with HIV, bone metabolism and not related to HTLV- associated myelopathy/ tropical spastic paraparesis (HAM/TSP) or adult T cell leukemia/lymphoma (ATL) were excluded.Results:Twenty-three studies were selected and sixteen studies were included in the review (eight experimental studies, three case reports, three cases series, one cross-sectional study and one review). Fourteen studies were focused on ATL, and two on HAM/TSP. The available data show thatin vitroexposure to 1,25(OH)2D inhibits proliferation of HTLV-infected lymphocytes in patients with ATL or HAM/TSP. It has been observed that hypercalcemia, the main cause of death in patients with ATL, is not associated with serum levels of 1,25(OH)2D or parathyroid hormone-related protein, but leukemia inhibitory factor/D factor seems to be an important factor for hypercalcemia pathogenesis. It was also demonstrated an association between the VDRApaIgene polymorphism and a decreased risk of HAM/TSP in HTLV positive individuals.Conclusion:Despite the small number and heterogeneity of the studies, this systematic review suggests that vitamin D play a role in the pathogenesis of HTLV-associated diseases.

Thymoquinone enhances the anticancer activity of doxorubicin against adult T-cell leukemia in vitro and in vivo through ROS-dependent mechanisms

AimsAdult T-cell leukemia (ATL) is a mature T-cell neoplasm associated with human T-cell lymphotropic virus (HTLV-1) infection. Major limitations in Doxorubicin (Dox) chemotherapy are tumor resistance and severe drug complications. Here, we combined Thymoquinone (TQ) with low concentrations of Dox and determined anticancer effects against ATL in cell culture and animal model. Main methodsHTLV-1 positive (HuT-102) and HTLV-1 negative (Jurkat) CD4+ malignant T-cell lines were treated with TQ, Dox and combinations. Viability and cell cycle effects were determined by MTT assay and flow cytometry analysis, respectively. Combination effects on mitochondrial membrane potential and generation of reactive oxygen species (ROS) were assessed. Expression levels of key cell death proteins were investigated by western blotting. A mouse xenograft model of ATL in NOD/SCID was used for testing drug effects and tumor tissues were stained for Ki67 and TUNEL. Key findingsTQ and Dox caused greater inhibition of cell viability and increased sub-G1 cells in both cell lines compared to Dox or TQ alone. The combination induced apoptosis by increasing ROS and causing disruption of mitochondrial membrane potential. Pretreatment with N-acetyl cysteine (NAC) or pan caspase inhibitor significantly inhibited the apoptotic response suggesting that cell death is ROS- and caspase-dependent. TQ and Dox combination reduced tumor volume in NOD/SCID mice more significantly than single treatments through enhanced apoptosis without affecting the survival of mice. SignificanceOur combination model offers the possibility to use up to twofold lower doses of Dox against ATL while exhibiting the same cancer inhibitory effects.

Differentiating Lung Involvement in Adult T-Cell Leukemia Lymphoma (ATLL) Versus HTLV Infection: Results from a Large Single-Center Cohort with Implications for Staging and Response Criteria

Introduction: Human T-cell lymphotropic virus (HTLV) is a retrovirus that has been associated with adult-T cell leukemia/lymphoma (ATLL) and other inflammatory conditions. Pulmonary involvement has not been widely associated to HTLV infection; however, high rates of imaging abnormalities in patients with and without ATLL have been reported. Okada reported 30%, 69% and 94% of abnormalities in HTLV1 carriers, ATLL and patients that transformed into ATLL. Whether these abnormalities follow a pattern related to each condition individually has not been defined. Hence, we undertook a retrospective study in ATLL and HTLV infected patients to determine the lung abnormalities which could be due to ATLL involvement rather than HTLV infection.Objectives: To compare the CT pulmonary findings among patients with HTLV infection with and without ATLL diagnosed at Montefiore Medical Center between 2004 and 2017.Methods: Patients diagnosed with HTLV infection by ICD9 were identified using the software Clinical Looking Glass and those with an available chest CT scan were selected. Data regarding demographics, smoking history, prior pulmonary conditions, HTLV and ATLL-associated characteristics was collected by chart review. CT chest was reviewed by an expert radiologist who was unaware of the patient diagnosis (ATLL versus non-ATLL) and findings were compared among groups. The staging CT scan was used to determine baseline pulmonary findings in patients with ATLL and the first CT chest around HTLV diagnosis was used for HTLV patients.Results: A total of 97 patients (72 with ATLL and 25 with HTLV alone) were identified. Mean age at HTLV diagnosis was 58.4 years (range: 33-88), 54.6% were females, 72.2% were Black Non-Hispanics while 27.8% were Hispanic. 88.3% were from Caribbean origin. Smoking history was similar between ATLL and non-ATLL groups (12% vs 8%, p=0.07) with no cases of prior active TB infection. Abnormal CT chest findings were present in 92.8%, 94.4% and 88% for the total cohort, ATLL and non-ATLL patients.Among patients with ATLL, 52.1% had acute and 43.7% had lymphomatous types; while only 1.4% and 2.8% had smoldering and chronic type. The most common CT chest findings were lymphadenopathy (50, 69.4%); followed by 3-10 mm nodules (32, 44.4%), ground-glass opacity, pleural effusion (31, 43.1% each), centrilobular nodules (28, 39.4%), thickening of interlobular septum (23, 31.9%) and bronchiectasis (18, 25%). Compared to the acute subtype, patients with lymphomatous subtype had higher rates of lymphadenopathy (83.9% vs 64.9, p=0.07) and lower rates of bronchiectasis (16.1% vs 35.1%, p=0.07).Among patients with non-ATLL, HTLV infection was diagnosed at an older age (63.8 vs. 56.6 years, p=0.03); HTLV-associated comorbidities were found in 16 cases (64%). Of these, myelopathy was the most frequent (10, 40%), followed by strongyloides (4, 16%). After HTLV diagnosis, CT chest was indicated in 28% patients for otherwise unexplained respiratory symptoms and to evaluate lung nodules or other chest X-ray abnormalities in 24% of cases. Bronchiectasis was the most common finding (12, 48%) followed by pleural thickening (11, 44%), ground-glass opacity and thickening of interlobular septum (10, 40%, each). Persistent abnormalities on follow-up imaging were present in 86.7% of the cases. Among patients with HTLV infection, those with ATLL were more likely to have nodules and lymphadenopathy (41.7% vs 20%, p=0.05 and 69.4% vs 24%, p<0.001, respectively) while bronchiectasis and pleural thickening was more likely in patients without ATLL (48% vs 25%, p=0.03 and 44% vs 23.6%, p=0.05; respectively).Conclusions: Pulmonary findings are highly prevalent in CT chest of patients with HTLV infection with and without ATLL. Bronchiectasis and pleural thickening was more frequently encountered in non-ATLL patients while lymphadenopathy and nodules were common finding in patients with ATLL. Pulmonary involvement in lymphoma is usually characterized by nodules and lymphadenopathy but patients with ATLL had a higher incidence of findings including ground glass opacities, bronchiectasis and interlobular septal thickening possibly due to their underlying HTLV infection. Based on this data, nodules and lymphadenopathy should be classified as ATLL involvement of the lung while other findings described here could be due to HTLV infection. These findings are important in staging and response criteria for ATLL. [Display omitted] DisclosuresJanakiram:Seatle Genetics: Membership on an entity's Board of Directors or advisory committees.

A Survey on Human T-cell Lymphotropic Virus Type 1 (HTLV-1) and Xenotropic Murine Leukemia Virus-Related Virus (XMRV) Coinfection in Tehran, Iran.

Background:Xenotropic murine leukemia virus-related virus (XMRV) is a gamma retrovirus, which has been detected in patients with prostate cancer, chronic fatigue syndrome, and general population with a number of acquired infections such as infection with human T-cell lymphotropic virus (HTLV) and human immunodeficiency virus (HIV). The aim of this study was to determine the HTLV-1 and XMRV coinfection for the first time in Iranian patients who were admitted to the Tehran hospitals.Materials and Methods:Two hundred and ninety one patients suspected with HTLV-1 were referred to the hospitals affiliated to the Iran University of Medical Sciences, Tehran, Iran from April 2012 to October 2016. Genomic deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) from peripheral blood mononuclear cells/cerebrospinal fluids was extracted by High Pure Viral Nucleic Acid Kit (Roche, Germany). After complementary DNA synthesis, conventional reverse transcriptase polymerase chain reaction was used for the detection of HTLV-1 or XMRV-infected patients. Statistical Package for Social Sciences (SPSS) software, version 16 (SPSS, Chicago, IL, USA) was used for statistical analyses.Results:Of the 291 patients suspected of HTLV infection, 123 (42.3%) were male with a mean age of 38±15 years. HTLV-1 RNA was found in 93 (31.9%) specimens comprising 40 men (41.3%) and 53 women (56.9%). Of the 93 patients who were HTLV-1 positive, one sample (1%) was positive for XMRV env gene.Conclusion:These findings suggest that the lack of significant detection of XMRV in patients who were HTLV-1 positive could not be associated with complications of HTLV-1. Although this is a preliminary report from Iranian patients with HTLV-1, further studies are needed to show the actual prevalence of XMRV infection by geographical distribution and various populations.

A comparative study of human T-cell lymphotropic virus-associated myelopathy in HIV-positive and HIV-negative patients in KwaZulu-Natal

Background: KwaZulu-Natal is an endemic area for HIV and human T-cell lymphotropic virus (HTLV) infection. The main neurological manifestation of HTLV is HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The effect of HIV co-infection in patients with HAM/TSP is not well documented.Aims: To determine the prevalence of HIV seropositivity in patients with HAM/TSP and compare the clinical, laboratory and radiological features of patients mono-infected with HTLV and those dually infected with HTLV and HIV.Methods: Adult patients referred to the Neurology Department at Inkosi Albert Luthuli Central Hospital in KwaZulu-Natal, South Africa, for the period 01 January 2004 to 31 December 2015 with a positive HTLV serology were identified from the National Health Laboratory Service database. A retrospective chart review was conducted to identify all patients who had a diagnosis of HAM/TSP and to record their HIV status. Clinical, laboratory and radiological data were compared for HIV-positive and HIV-negative patients.Results: A total of 52 patients with HAM/TSP were identified. HIV results were available in 44 patients of whom 23 (52%) patients were HIV co-infected. Patients who were HIV-positive had a younger age of presentation compared to HIV-negative patients (median: 31 vs 50 years, p = 0.002). HIV-positive patients had a median duration of symptoms at presentation of 12 months compared to 16 months for HIV-negative patients, but the difference did not reach statistical significance (p = 0.082). The CD4 cell counts of HIV-positive patients were well preserved with a median count of 781 cells/µL.Conclusions: HIV co-infection is commonly seen in the setting of HAM/TSP in KwaZulu-Natal. An interaction between the viruses may accelerate the development of HAM/TSP, leading to a younger age of presentation. Co-infection may have treatment implications because of CD4 counts being preserved in these patients.

Reconsideration of blood donation testing strategy for human T-cell lymphotropic virus in Australia.

Universal testing of blood donations for human T-cell lymphotropic virus (HTLV) in Australia may no longer be appropriate given the low prevalence of HTLV infection and the mitigating effect of universal leucodepletion for cellular components. This study aimed to determine the most appropriate HTLV testing strategy using the Risk-Based Decision-Making Framework for Blood Safety. The risk of HTLV transfusion-transmission using three testing strategies (universal, new-donor and no testing) and cost-effectiveness of the first two strategies were assessed using adaptations of published mathematical models. The overall prevalence for 2004-2014 was three HTLV-positives per million donations. It was estimated that annually, universal testing incurred a cost of approximately AUD $3 million and prevented 83 HTLV-positive cellular components from being issued, and new-donor testing cost approximately $225000 and prevented 81 components. The number of cases of transfusion-transmitted HTLV and HTLV-associated disease prevented per year by universal and new-donor testing was essentially equivalent. According to preset risk thresholds, the risk of transfusion-transmission was negligible for universal and new-donor testing, and minimal without testing. Transfusion-transmission of HTLV is a minimal risk in Australia even without testing. However, any revision of testing strategy must consider not only risk and cost-effectiveness, but also stakeholder, ethical and regulatory perspectives. Considering all relevant criteria, new-donor testing is judged the optimal strategy because it is able to achieve almost the same outcomes as universal testing, at a fraction of the cost.