Refining the risk of HTLV-1-associated myelopathy in people living with HTLV-1: identification of a HAM-like phenotype in a proportion of asymptomatic carriers.

Up to 3.8% of human T-lymphotropic virus type-1 (HTLV-1)-infected asymptomatic carriers (AC) eventually develop HTLV-1-associated myelopathy (HAM). HAM occurs in patients with high (> 1%) HTLV proviral load (PVL). However, this cut-off includes more than 50% of ACs and therefore the risk needs to be refined. As HAM is additionally characterised by an inflammatory response to HTLV-1, markers of T cell activation (TCA), ß2-microglobulin (ß2M) and neuronal damage were accessed for the identification of ACs at high risk of HAM. Retrospective analysis of cross-sectional and longitudinal routine clinical data examining differences in TCA (CD4/CD25, CD4/HLA-DR, CD8/CD25 & CD8/HLA-DR), ß2M and neurofilament light (NfL) in plasma in ACs with high or low PVL and patients with HAM. Comparison between 74 low PVL ACs, 84 high PVL ACs and 58 patients with HAM revealed a significant, stepwise, increase in TCA and ß2M. Construction of receiver operating characteristic (ROC) curves for each of these blood tests generated a profile that correctly identifies 88% of patients with HAM along with 6% of ACs. The 10 ACs with this 'HAM-like' profile had increased levels of NfL in plasma and two developed myelopathy during follow-up, compared to none of the 148 without this viral-immune-phenotype. A viral-immuno-phenotype resembling that seen in patients with HAM identifies asymptomatic carriers who are at increased risk of developing HAM and have markers of subclinical neuronal damage.

Wnt3 Is Lipidated at Conserved Cysteine and Serine Residues in Zebrafish Neural Tissue.

Wnt proteins are a family of hydrophobic cysteine-rich secreted glycoproteins that regulate a gamut of physiological processes involved in embryonic development and tissue homeostasis. Wnt ligands are post-translationally lipidated in the endoplasmic reticulum (ER), a step essential for its membrane targeting, association with lipid domains, secretion and interaction with receptors. However, at which residue(s) Wnts are lipidated remains an open question. Initially it was proposed that Wnts are lipid-modified at their conserved cysteine and serine residues (C77 and S209 in mWnt3a), and mutations in either residue impedes its secretion and activity. Conversely, some studies suggested that serine is the only lipidated residue in Wnts, and substitution of serine with alanine leads to retention of Wnts in the ER. In this work, we investigate whether in zebrafish neural tissues Wnt3 is lipidated at one or both conserved residues. To this end, we substitute the homologous cysteine and serine residues of zebrafish Wnt3 with alanine (C80A and S212A) and investigate their influence on Wnt3 membrane organization, secretion, interaction and signaling activity. Collectively, our results indicate that Wnt3 is lipid modified at its C80 and S212 residues. Further, we find that lipid addition at either C80 or S212 is sufficient for its secretion and membrane organization, while the lipid modification at S212 is indispensable for receptor interaction and signaling.

Bisindolemethane derivatives as highly potent anticancer agents: Synthesis, medicinal activity evaluation, cell-based compound discovery, and computational target predictions.

In recent years chemical and biological interest in Turbomycin B and its various analogues have motivated researchers to develop new bioactive indole scaffolds. In this work, we focused on the development of indole alkaloids, especially bioindolemethane derivatives and their anticancer potential. Based on the excellent IC50 value against HeLa and A549 cell, cyano-substituted Turbomycin B (CN-TBM) was selected to understand the mechanism behind cancer cell death. The potential targets involved in CN-TBM mediated apoptotic cell death were predicted by comparing the results of two chemoinformatic approaches, i.e., PharmMapper and IdTarget. Four targets were predicted using these tools and the targets were further subjected to molecular docking to obtain a single target for CN-TBM. Serine/threonine-protein kinase (Pim-1) was identified as the direct target of CN-TBM with a pharmacophore model complementing well with the molecular features of CN-TBM. The interaction between CN-TBM and Pim-1 was well supported by high fit-score, Z-score, idTarget dock score and excellent binding affinity. Further, the present study also provides an insight into co-expression, shared protein domains, functional annotation and relationship within the ten putative targets of CN-TBM predicted by PharmMapper.

Self-Flagellation as Possible Route of Human T-Cell Lymphotropic Virus Type-1 Transmission.

We report human T-cell lymphotropic virus type 1 infection associated with self-flagellation in 10 UK residents. These persons were heterosexual men from Pakistan, India, and Iraq. One person showed seroconversion in adulthood; 1 was co-infected with hepatitis C virus. No other risk factors for bloodborne virus acquisition were identified. Onward sexual transmission has occurred.

Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer.

Multidrug resistance (MDR) is the major cause, by which cancer cells expel the drugs out, developing a challenge against the current chemotherapeutic drugs regime. This mechanism is attributed to the over expression of ABC transporters like MRP1 on the surface of cells. Since nucleotide binding domains (NBD) of ABC transporters are the site of ATP binding and hydrolysis, thereby in this study we have targeted NBD1 of MRP1using molecular docking and molecular dynamic simulations (MDS). The compounds present in the FDA approved library were docked against NBD1 of the human multidrug resistance associated protein 1 (PDB ID: 2CBZ). For the docking studies, Standard Precision and Extra Precision methods were employed. After the EP docking studies, ligands showed an extremely low docking score that was indicative of very high binding affinity of the ligands to the NBD. Apart from the low docking score, another short listing criterion in simulation studies was the interaction of incoming ligand with the desired conserved residues of NDB involved in ATP binding and hydrolysis. Based on these measures, potassium citrate (DB09125) and technetium Tc-99m medronate (DB09138) were chosen and subjected to 100 ns simulation studies. From the MDS study we concluded that between these two compounds, potassium citrate is a better candidate for targeting MRP1.

Human T-cell lymphotropic virus (HTLV)-associated encephalopathy: an under-recognised cause of acute encephalitis? Case series and literature review.

Human T-cell lymphotropic virus (HTLV)-1-associated myelopathy (HAM) is well described. Clinical features are predominantly consistent with cord pathology, though imaging and autopsy studies also demonstrate brain inflammation. In general, this is subclinical; however, six cases have previously been reported of encephalopathy in HTLV-1-infected patients, without alternative identified aetiology. We describe three further cases of encephalitis in the UK HAM cohort (n = 142), whereas the annual incidence of acute encephalitis in the general population is 0.07-12.6 per 100,000. Clinical features included reduced consciousness, fever/hypothermia, headaches, seizures, and focal neurology. Investigation showed: raised CSF protein; pleocytosis; raised CSF:peripheral blood mononuclear cell HTLV-1 proviral load ratio; and MRI either normal or showing white matter changes in brain and cord. Four of the six previous case reports of encephalopathy in HTLV-infected patients also had HAM. Histopathology, reported in three, showed perivascular predominantly CD8+ lymphocytic infiltrates in the brain. One had cerebral demyelination, and all had cord demyelination. We have reviewed the existing six cases in the literature, together with our three new cases. In all seven with HAM, the spastic paraparesis deteriorated sub-acutely preceding encephalitis. Eight of the nine were female, and four of the seven treated with steroids improved. We propose that HTLV-associated encephalopathy may be part of the spectrum of HTLV-1-induced central nervous system disease.

Effect of Pulsed Methylprednisolone on Pain, in Patients with HTLV-1-Associated Myelopathy.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune mediated myelopathy caused by the human T-lymphotropic virus type 1 (HTLV-1). The efficacy of treatments used for patients with HAM/TSP is uncertain. The aim of this study is to document the efficacy of pulsed methylprednisolone in patients with HAM/TSP. Data from an open cohort of 26 patients with HAM/TSP was retrospectively analysed. 1g IV methylprednisolone was infused on three consecutive days. The outcomes were pain, gait, urinary frequency and nocturia, a range of inflammatory markers and HTLV-1 proviral load. Treatment was well tolerated in all but one patient. Significant improvements in pain were: observed immediately, unrelated to duration of disease and maintained for three months. Improvement in gait was only seen on Day 3 of treatment. Baseline cytokine concentrations did not correlate to baseline pain or gait impairment but a decrease in tumour necrosis factor-alpha (TNF-α) concentration after pulsed methylprednisolone was associated with improvements in both. Until compared with placebo, treatment with pulsed methylprednisolone should be offered to patients with HAM/TSP for the treatment of pain present despite regular analgesia.

Human T-lymphotropic virus/HIV co-infection: a clinical review.

PURPOSE OF REVIEW: Human T-lymphotropic virus (HTLV)/HIV co-infections are often undiagnosed, with important clinical implications. The literature is relatively sparse with key observations derived in the pre-highly-active antiretroviral therapy era. RECENT FINDINGS: The epidemiology of co-infection, the impact of each virus on the other, with particular reference to clinical manifestations and the impact of antiretroviral therapy on HTLVs are described. SUMMARY: Important clinical effects of HTLV/HIV co-infection include the higher rates of myelopathy and other neurological disorders and the poor predicative value of CD4+ cell counts as a surrogate for immune suppression. Current antiretroviral therapies in isolation have no proven effect on HTLV-1/2 proviral load.