HTLV-1: the silent impact revealed Cook, Lucy B M; Taylor, Graham P
The Lancet infectious diseases,
January 2020, 2020-Jan, 2020-01-00, 20200101, Letnik:
20, Številka:
1
Journal Article
Recenzirano
The seminal publication in The Lancet Infectious Diseases by Gill Schierhout and colleagues looking at disease outcomes for which HTLV-1 is not a necessary diagnostic criterion shows that morbidity ...and mortality are clearly associated with HTLV-1 infection.5 The authors report a 57% increased risk of premature death that is independent of adult T-cell leukaemia-lymphoma (ATL) and HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP), the two well known HTLV-1-associated diseases that require HTLV-1 as a prerequisite to their diagnosis. ...a change in perception of the public health importance of HTLV-1 including cost–benefit analyses, by region, of screening programmes. ...better funding to address the huge gaps in pathogenesis and treatment.
A new paradigm for the management of ATL Taylor, Graham P.; Cook, Lucy B.
British journal of haematology,
September 2022, Letnik:
198, Številka:
6
Journal Article
Fragmented genomic DNA is constitutively released from dying cells into interstitial fluid in healthy tissue. In cancer, this so-called 'cell-free' DNA (cfDNA) released from dying malignant cells ...encodes cancer-associated mutations. Thus, minimally invasive sampling of cfDNA in blood plasma can be used to diagnose, characterise and longitudinally monitor solid tumours at remote sites in the body. ~5% of carriers of Human T cell leukaemia virus type 1 (HTLV-1) develop Adult T cell leukaemia/lymphoma (ATL), and a similar percentage develop an inflammatory CNS disease, HTLV-1 associated myelopathy (HAM). In both ATL and HAM, high frequencies of HTLV-1 infected cells are present in the affected tissue: each carrying an integrated DNA copy of the provirus. We hypothesised that turnover of infected cells results in the release of HTLV-1 proviruses in cfDNA, and that analysis of cfDNA from infected cells in HTLV-1 carriers might contain clinically useful information pertaining to inaccessible sites in the body- e.g. for early detection of primary or relapsing localised lymphoma type ATL. To evaluate the feasibility of this approach, we tested for HTLV-1 proviruses in blood plasma cfDNA.
CfDNA (from blood plasma) and genomic DNA (gDNA, from peripheral blood mononuclear cells, PBMC) was isolated from blood from 6 uninfected controls, 24 asymptomatic carriers (AC), 21 patients with HAM and 25 patients with ATL. Proviral (HTLV-1
) and human genomic DNA (the beta globin gene,
) targets were quantified by qPCR using primer pairs optimised for fragmented DNA.
Pure, high quality cfDNA was successfully extracted from blood plasma of all study participants. When compared with uninfected controls, HTLV-1 carriers had higher concentrations of cfDNA circulating in their blood plasma. Patients with ATL who were not in remission had the highest levels of blood plasma cfDNA in any group studied. HTLV-1 proviral DNA was detected in 60/70 samples obtained from HTLV-1 carriers. The proviral load (percentage of cells carrying proviruses) was approximately tenfold lower in plasma cfDNA than in PBMC genomic DNA, and there was a strong correlation between the proviral load in cfDNA and PBMC genomic DNA in HTLV-1 carriers that did not have ATL. cfDNA samples in which proviruses were undetectable also had very low proviral load in PBMC genomic DNA. Finally, detection of proviruses in cfDNA of patients with ATL was predictive of clinical status: patients with evolving disease had higher than expected total amount of proviruses detectable in plasma cfDNA.
We demonstrated that (1) HTLV-1 infection is associated with increased levels of blood plasma cfDNA, (2) proviral DNA is released into blood plasma cfDNA in HTLV-1 carriers and (3) proviral burden in cfDNA correlates with clinical status, raising the possibility of developing assays of cfDNA for clinical use in HTLV-1 carriers.
Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL ...remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches.
Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology-Human T-Lymphotropic Virus and Related Retroviruses-in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents.
As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (> 90% agreement).
This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL.
Most T cell receptor (TCR)Vβ chain-expressing T cell lymphomas (TCL) including those caused by Human T cell leukaemia virus type-1 (HTLV-1) have poor prognosis. We hypothesised that chimeric antigen ...receptor (CAR)-mediated targeting of the clonal, lymphoma-associated TCRβ chains would comprise an effective cell therapy for TCL that would minimally impact the physiological TCR repertoire.
As proof of concept, we generated CAR constructs to target four TCRVβ subunits. Efficacy of the CAR constructs was tested using conventional T cells as effectors (CAR-T). Since invariant NKT (iNKT) cell do not incite acute graft-versus-host disease and are suitable for 'off-the-shelf' immunotherapy, we generated anti-TCRVβ CAR-iNKT cells.
We show that anti-TCRVβ CAR-T cells selectively kill their cognate tumour targets while leaving >90% of the physiological TCR repertoire intact. CAR-iNKT cells inhibited the growth of TCL
, and were also selectively active against malignant cells from Adult T cell leukaemia/lymphoma patients without activating expression of HTLV-1.
Thus we provide proof-of-concept for effective and selective anti-TCRVβ CAR-T and -iNKT cell-based therapy of TCL with the latter providing the option for 'off-the-shelf' immunotherapy.
HTLV-1: Persistence and pathogenesis Cook, Lucy B; Elemans, Marjet; Rowan, Aileen G ...
Virology (New York, N.Y.),
01/2013, Letnik:
435, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Highlights ► General method to identify the determinants of protective immunity and its application to HTLV-1. ► Observation made that “innate” KIR receptors enhance the HLA class I-restricted ...response in HTLV-1 infection. ► Description of the mechanisms of HTLV-1 persistence and of the importance of the viral protein HBZ. ► Observation made that CD8+ T cells kill infected, Tax-expressing cells in vivo at a slow rate. ► Description of the role of the HTLV-1 proviral integration site.
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