HTLV-1: Regulating the Balance Between Proviral Latency and Reactivation

HTLV-1 plus-strand transcription begins with the production of doubly-spliced tax/rex transcripts, the levels of which are usually undetectable in freshly isolated peripheral blood mononuclear cells (PBMCs) from HTLV-1-infected individuals. However, the presence of a sustained chronically active cytotoxic T-cell response to HTLV-1 antigens in virtually all HTLV-1-infected individuals, regardless of their proviral load, argues against complete latency of the virus in vivo. There is an immediate burst of plus-strand transcription when blood from infected individuals is cultured ex vivo. How is the HTLV-1 plus strand silenced in PBMCs? Is it silenced in other anatomical compartments within the host? What reactivates the latent provirus in fresh PBMCs? While plus-strand transcription of the provirus appears to be intermittent, the minus-strand hbz transcripts are present in a majority of cells, albeit at low levels. What regulates the difference between the 5′- and 3′-LTR promoter activities and thereby the tax-hbz interplay? Finally, T lymphocytes are a migratory population of cells that encounter variable environments in different compartments of the body. Could these micro-environment changes influence the reactivation kinetics of the provirus? In this review we discuss the questions raised above, focusing on the early events leading to HTLV-1 reactivation from latency, and suggest future research directions

Is there a role for HTLV-1-specific CTL in adult T-cell Leukemia/Lymphoma?

ATLL is an aggressive malignancy of T cells that affects about 5% of individuals infected with HTLV-1. The precise mechanism of oncogenesis is not known, but there is evidence that two regulatory viral proteins, Tax and HBZ, are involved. A high set point proviral load is associated with development of ATLL or a chronic inflammatory condition, HAM/TSP. Several lines of evidence, including HLA class 1 association studies and in vitro killing assays, indicate that cytotoxic T lymphocytes are instrumental in determining this proviral load set point. Prior studies have focused chiefly on the CTL response to the immunodominant Tax protein: efficient lysis of Tax-expressing cells inversely correlates with proviral load in nonmalignant infection. However, a recent study showed that strong binding of peptides from HBZ, but not Tax, to HLA class 1 molecules was associated with a low proviral load and a reduced risk of developing HAM/TSP, indicating an important role for HBZ-specific CTL in determining infection outcome. In comparison with nonmalignant infection, HTLV-1-specific CTLs in ATLL patients are reduced in frequency and functionally deficient. Here we discuss the nature of protective CTL responses in nonmalignant HTLV-1 infection and explore the potential of CTLs to protect against ATLL

How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)?

A typical person infected with the retrovirus human T-lymphotropic virus type 1 (HTLV-1) carries tens of thousands of clones of HTLV-1-infected T lymphocytes, each clone distinguished by a unique integration site of the provirus in the host genome. However, only 5% of infected people develop the malignant disease adult T cell leukaemia/lymphoma, usually more than 50 years after becoming infected. We review the host and viral factors that cause this aggressive disease

Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy

Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety

Well-being of police custody staff: a multi strategy-approach across seven police forces

British police custody is one of the most challenging of police environments, with the treatment of prisoners a source of public and media concern, especially regarding deaths in police custody; and where every action by staff is recorded audibly and visually. These kinds of issues threaten staff well-being (measured as role well-being, low workplace stress, mental and subjective well-being, energy and engagement). To address these issues, the study targeted five roles of custody inspector/sergeant, detention officer (public and private) and custody officer assistant in a four-wave panel survey of seven English police forces (with each separated by a lag of five months). Study engagement was 333 (a response rate of 46.57%) across 33 custody sites which, together with repeated returns, provided a quantitative data set of 370. In addition, self-report open comments at the end of surveys and other communications, numbered 178 (i.e. 131 from the current study and 47 from earlier custody-related research). This provided the study with an original multi-strategy approach that was: 1) Quantitative. Informed by an expanded version of a model first introduced in Werner-de-Sondberg et al. (2018); instrumental in identifying cultural subcomponent tensions, influential mediator and moderator relationships, contrasting role well-being and negatively affective vulnerabilities; 2) Qualitative. Conducted as a thematic analysis of self-report open (survey) comments and other communications, where quantitative results were explained deductively and inductively; and 3) Quantitative and qualitative. Where a single (embedded) case study identified eight propositions to be supported or rejected regarding: police custody (officer and police staff) vulnerability/ability to cope; status of custody; staffing levels; ITS inadequacies; large new-build custody sites; twelve hour shifts and private sector outsourcing. In addition, a multiple case study identified five synthesised crosscases in terms of similarity and difference. The study concluded by discussing a range of issues: theoretical; methodological; reflexive; practical; and future focused

Crystal Structure of the ZrO Phase at Zirconium/Zirconium Oxide Interfaces

Zirconium-based alloys are used in water-cooled nuclear reactors for both nuclear fuel cladding and structural components. Under this harsh environment, the main factor limiting the service life of zirconium cladding, and hence fuel burn-up efficiency, is water corrosion. This oxidation process has recently been linked to the presence of a sub-oxide phase with well-defined composition but unknown structure at the metal–oxide interface. In this paper, the combination of first-principles materials modeling and high-resolution electron microscopy is used to identify the structure of this sub-oxide phase, bringing us a step closer to developing strategies to mitigate aqueous oxidation in Zr alloys and prolong the operational lifetime of commercial fuel cladding alloys

Early nephrology care provided by the nephrologist alone is not sufficient to mitigate the social and psychological aspects of chronic kidney disease

OBJECTIVE: Patients with chronic kidney disease who receive early nephrology care have a better prognosis with maintenance dialysis. We aimed to determine whether early referral to a nephrologist can also improve the psychological burden of having chronic kidney disease. SUBJECTS AND METHODS: Thirty-nine patients with chronic kidney disease that required hemodialysis were studied: 19 had a $ 6-month history of nephrology care (Group1), and 20 had never received any prior nephrology care (Group2). All patients participated in a semi-structured interview that addressed their perceived knowledge and psychological aspects related to CKD and hemodialysis. Demographic and laboratory data as well as socioeconomic status were evaluated. RESULTS: In both groups, most of the patients were of low socioeconomic status. Group 1 had significantly better laboratory parameters (p<0.05). The patients' answers to the questions showed no differences between the groups: 63% of Group 1 and 55% of Group 2 reported that they had no prior knowledge about dialysis; 58% and 40%, respectively, reported that they ''don't completely understand what the doctor says''; and 74% and 85%, respectively, believed that their ''kidneys would work again''. CONCLUSION: Pre-dialysis nephrology care improves the clinical conditions of the patients with chronic kidney disease but is insufficient for minimizing other aspects of having chronic kidney disease

Wide-field phase imaging for the endoscopic detection of dysplasia and early-stage esophageal cancer

© 2018 SPIE. Esophageal cancer has a 5-year survival rate below 20%, but can be curatively resected if it is detected early. At present, poor contrast for early lesions in white light imaging leads to a high miss rate in standard-of-care endoscopic surveillance. Early lesions in the esophagus, referred to as dysplasia, are characterized by an abundance of abnormal cells with enlarged nuclei. This tissue has a different refractive index profile to healthy tissue, which results in different light scattering properties and provides a source of endogenous contrast that can be exploited for advanced endoscopic imaging. For example, point measurements of such contrast can be made with scattering spectroscopy, while optical coherence tomography generates volumetric data. However, both require specialist interpretation for diagnostic decision making. We propose combining wide-field phase imaging with existing white light endoscopy in order to provide enhanced contrast for dysplasia and early-stage cancer in an image format that is familiar to endoscopists. Wide-field phase imaging in endoscopy can be achieved using coherent illumination combined with phase retrieval algorithms. Here, we present the design and simulation of a benchtop phase imaging system that is compatible with capsule endoscopy. We have undertaken preliminary optical modelling of the phase imaging setup, including aberration correction simulations and an investigation into distinguishing between different tissue phantom scattering coefficients. As our approach is based on phase retrieval rather than interferometry, it is feasible to realize a device with low-cost components for future clinical implementation

Sector well-being differences among UK police custody staff

The research explores a new model of staff well-being across UK police custodial services (public and private). These services are unique for the fact that police sergeant custody officers are supported by detention officers who can be publicly or privately contracted, with the latter providing a heterogeneous mix never previously researched. The model informs a survey approach conducted across four English police forces. Drawing on a diverse literature which compares health and criminal justice professions, this study explores the possibility that private sector detention officers will report lower levels of emotional exhaustion and workplace stress and higher levels of personal accomplishment than their public sector counterparts. Multilevel analyses, supplemented by ANOVA and t tests, detected statistically significant differences for private sector detention officers regarding higher levels of emotional exhaustion and lower levels of personal accomplishment and workplace stress (with the stress result the only one in the predicted direction). However, results should be interpreted as sample specific linked to privately contracted detention officer disquiet with their then employer (since replaced). That said, the results provide a good exploration of the model's utility together with important lessons for model and survey development in the future

Genome-wide Determinants of Proviral Targeting, Clonal Abundance and Expression in Natural HTLV-1 Infection

The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression of the provirus, which in turn determines the abundance and pathogenic potential of infected T cell clones in vivo. We recently developed a high-throughput method for the genome-wide amplification, identification and quantification of proviral integration sites. Here, we used this protocol to test two hypotheses. First, that binding sites for transcription factors and chromatin remodelling factors in the genome flanking the proviral integration site of HTLV-1 are associated with integration targeting, spontaneous proviral expression, and in vivo clonal abundance. Second, that the transcriptional orientation of the HTLV-1 provirus relative to that of the nearest host gene determines spontaneous proviral expression and in vivo clonal abundance. Integration targeting was strongly associated with the presence of a binding site for specific host transcription factors, especially STAT1 and p53. The presence of the chromatin remodelling factors BRG1 and INI1 and certain host transcription factors either upstream or downstream of the provirus was associated respectively with silencing or spontaneous expression of the provirus. Cells expressing HTLV-1 Tax protein were significantly more frequent in clones of low abundance in vivo. We conclude that transcriptional interference and chromatin remodelling are critical determinants of proviral latency in natural HTLV-1 infection