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Anti-aquaporin 4 (AQP4) antibody is a marker of neuromyelitis optica (NMO) spectrum diseases, characteristically presenting with myelitis longitudinally extensive transverse myelitis or optic neuritis (ON). While cerebral lesions are recognized, extensive brain involvement and cognitive impairment is rare. We report a case of subacute encephalopathy associated with fulminant subcortical brain lesions. A 19-year-old Jamaican woman reported decreased sensation and power in the left leg, recovering over 2 weeks without medical investigation. Eight months later, she developed painless bilateral visual loss (no perception of light on right, counting fingers on left), treated with intravenous methylprednisolone and plasma exchange. Vision improved gradually to 1/60 (right) and 6/6 (left). Recurrent ON 10 months later reduced acuity to counting fingers bilaterally. With further methylprednisolone, and azathioprine commencement (100 mg/day, low dose because of lymphopenia), acuities improved over 2 months. However, another relapse reduced vision to hand movements bilaterally, necessitating further plasma exchange. Two months thereafter, she developed gait failure, worsening vision, confusion and aggression, severe executive dysfunction, impaired attention, memory and verbal fluency, and suffered a generalized tonic–clonic seizure. There was no perception of light bilaterally, spastic paraparesis and hemisensory loss. With no response to further methylprednisolone and plasma exchange, she was given rituximab (375 mg/kg weekly for 4 weeks). Despite this, 2 weeks later she developed flaccid paraplegia with an extensive cord lesion from cervical to L1 vertebral segments. She remains profoundly disabled; blind, paraplegic, and with impaired comprehension. AQP4-IgG antibody titers were extremely high (maximal level 1:45,000 dilution). Double-stranded DNA antibodies (244 IU/l) and pANCA staining (myeloperoxidase antibody negative) were found. Cerebrospinal fluid (CSF) showed \3 white cells/ll, with normal protein (0.17 g/l). Oligoclonal bands were present in CSF, but not in blood. Antibodies to human T cell lymphotrophic virus (HTLV-1) were present in blood. Viral load was three HTLV-1 DNA copies per 100 peripheral blood mononuclear cells (3 % PBMCs) in blood and 14 % in CSF. MRI revealed T2-hyperintense changes in optic pathways, and numerous periventricular, callosal and juxtacortical white-matter lesions. Over 10 months, scans deteriorated (Fig. 1a, b). A brain biopsy, to exclude other treatable diagnoses, showed features consistent with necrotizing active demyelination (Fig. 1c, e, f; Fig. S1), and absence of AQP4 (Fig. 1d; Figs. S2, S3). Our patient presented with recurrent bilateral ON leading to blindness, and an evolving encephalopathy with necrotizing cerebral white matter destruction. Several features may explain this severity. Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6651-y) contains supplementary material, which is available to authorized users.

There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease., Author Summary Human T lymphotropic virus-1 infects T cells, causing them to multiply. In some people, cellular replication is unchecked, resulting in an aggressive blood cancer called adult T-cell leukemia/lymphoma. The virus proteins are efficiently recognised as ‘foreign’ by the immune system in most infected individuals. People with cancer have weak immune responses to certain viral proteins, however it was not known whether the immune system can attack the malignant cells in this disease. In this paper, we developed a method which allows us to directly monitor malignant cells, and used it to test whether malignant and non-malignant infected cells are killed by immune cells from people with the cancer. We found that some people had immune cells which could kill the cancer cells. These observations are both new and important because they raise the possibility of boosting the immune response to malignant cells as a novel therapeutic strategy for this aggressive and hard-to-treat disease.

BACKGROUND:Five to ten million persons, are infected by HTLV-1 of which 3% will develop HTLV-1-associated myelopathy (HAM) a chronic, disabling inflammation of the spinal cord. Walking, a fundamental, complex, multi-functional task is demanding of multiple body systems. Restricted walking ability compromises activity and participation levels in people with HAM (pwHAM). Therapy aims to improve mobility but validated measures are required to assess change. STUDY DESIGN:Prospective observational study. OBJECTIVES:To explore walking capacity in pwHAM, walking endurance using the 6 minute walk (6MW), and gait speed, using the timed 10m walk (10mTW). SETTING:Out-patient setting in an inner London Teaching hospital. METHODS:Prospective documentation of 10mTW and 6MW distance; walking aid usage and pain scores measured twice, a median of 18 months apart. RESULTS:Data analysis was completed for twenty-six pwHAM, (8♂; 18♀; median age: 57.8 years; median disease duration: 8 years). Median time at baseline to: complete 10m was 17.5 seconds, versus 21.4 seconds at follow up; 23% completed the 6MW compared to 42% at follow up and a median distance of 55m was covered compared to 71m at follow up. Using the 10mTW velocity to predict the 6MW distance, overestimated the distance walked in 6 minutes (p

Human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the CNS that causes weakness or paralysis of the legs, lower back pain and urinary symptoms. HAM/TSP was first described in Jamaica in the nineteenth century, but the aetiology of the condition, infection with the retrovirus HTLV-1, was only identified in the 1980s. HAM/TSP causes chronic disability and, accordingly, imposes a substantial health burden in areas where HTLV-1 infection is endemic. Since the discovery of the cause of HAM/TSP, considerable advances have been made in the understanding of the virology, immunology, cell biology and pathology of HTLV-1 infection and its associated diseases. However, progress has been limited by the lack of accurate animal models of the disease. Moreover, the treatment of HAM/TSP remains highly unsatisfactory: antiretroviral drugs have little impact on the infection and, although potential disease-modifying therapies are widely used, their value is unproved. At present, clinical management is focused on symptomatic treatment and counselling. Here, we summarize current knowledge on the epidemiology, pathogenesis and treatment of HAM/TSP and identify areas in which further research is needed. For an illustrated summary of this Primer, visit: http://go.nature.com/tjZCFM.

Adult T cell leukaemia / lymphoma (ATLL) is a mature (post thymic) T cell lymphoma caused by the human T-lymphotropic virus type 1 (HTLV-1) infection. Overall survival in the aggressive subtypes (Acute Leukaemia and Lymphomatous) remains poor in part due to chemotherapy resistance. To improve treatment outcome for de novo disease, better induction therapies are required and since the pathogenic agent is known it would seem sensible to target the virus. In a recent meta-analysis the use of zidovudine and interferon alpha (ZDV/IFN) has been associated with improved response rates and prolonged overall survival in leukemic subtypes of ATLL (both acute and Chronic) confirmed in a multivariate analysis. In a more recent UK study the overall response rate for patients with aggressive ATLL treated with chemotherapy alone was 49 % compared to 81 % with combined first line therapy (chemotherapy with concurrent or sequential ZDV/IFN). Combined first line therapy prolonged median OS in acute (p = 0.0081) and lymphomatous ATLL (p = 0.001).These data support the use of low dose ZDV/IFN with chemotherapy as first line treatment for patients with newly diagnosed aggressive ATLL. Although the mechanisms of action are incompletely understood, some possible explanations for their efficacy will be discussed.

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV)-positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection.

Adult T-cell leukaemia lymphoma (ATLL) is an aggressive T-cell malignancy caused by the human T-lymphotropic virus type-1 (HTLV-1) and is associated with a very poor prognosis. Combination chemotherapy has had little impact on the long term survival of these patients. ATLL cells are characterised by the expression of CD25 (IL-2Rα), which is not expressed in normal resting T-cells. Daclizumab (Zenapax(®)) is a humanised murine anti-CD25 monoclonal antibody, which contains 10% murine CDR sequences. In this prospective trial 15 patients with aggressive ATLL were treated with CHOP-Zenapax (CHOP-Z) to determine the tolerability and feasibility of this novel regimen as well as evaluate its efficacy. Eleven patients had acute ATLL and four had the lymphoma subtype. The main presenting features were elevated LDH (100%), lymphocytosis (73%), lymphadenopathy (67%), skin lesions (40%), hypercalcaemia (53%), and hepato-splenomegaly (27%). Ten (67%) patients received the six scheduled cycles. Complete response (CR) lasting for two months or more was seen in 5 (33%), partial response in 3 (20%), minor response in 1 (7%), and no response in 6 (40%) patients. The median overall survival was 10 months (95% CI: 0.05-20.88) but this was significantly longer among responders (18 months) compared to non responders (3 months) (P = 0.019). For patients who achieved CR the disease free survival (DFS) was 15 months while the event-free survival (EFS) was 5 months. In conclusion CHOP-Z is safe and in those who achieve a complete response it was associated with prolonged overall survival.

To prevent the transmission of HIV infection during the postpartum period, the British HIV Association and Children's HIV Association (BHIVA/CHIVA) continue to recommend the complete avoidance of breast feeding for infants born to HIV-infected mothers, regardless of maternal disease status, viral load or treatment.

Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1–associated diseases. Yet the reasons for the variation within and between persons in the abundance of HTLV-1–infected clones remain unknown. We devised a high-throughput protocol to map the genomic location and quantify the abundance of > 91 000 unique insertion sites of the provirus from 61 HTLV-1+ persons and > 2100 sites from in vitro infection. We show that a typical HTLV-1–infected host carries between 500 and 5000 unique insertion sites. We demonstrate that negative selection dominates during chronic infection, favoring establishment of proviruses integrated in transcriptionally silenced DNA: this selection is significantly stronger in asymptomatic carriers. We define a parameter, the oligoclonality index, to quantify clonality. The high proviral load characteristic of HTLV-1–associated inflammatory disease results from a larger number of unique insertion sites than in asymptomatic carriers and not, as previously thought, from a difference in clonality. The abundance of established HTLV-1 clones is determined by genomic features of the host DNA flanking the provirus. HTLV-1 clonal expansion in vivo is favored by orientation of the provirus in the same sense as the nearest host gene.

Human T-lymphotropic virus type 1 (HTLV-1), the first discovered human retrovirus, is prevalent in Japan, the Caribbean, parts of sub-Saharan Africa, South America, Melanesia, and the Middle East, with worldwide prevalence once estimated to be 10–20 million [1]. Infection with HTLV-1 is lifelong. Most subjects remain asymptomatic carriers (ACs), but a significant minority, 7%, will develop adult T cell leukemia/lymphoma (ATLL) [2] or HTLV-1-associated myelopathy (HAM) [3]. The overall risk of disease may reach 10% if HTLV-1–associated uveitis [4], HTLV-1-associated infective dermatitis [5], and other, apparently associated, manifestations such as polymyositis [6], a broad spectrum of lung disease [7], and thyroiditis [8] are included. In addition to these overt diseases, a reduction in life expectancy, of uncertain cause, has been described [5, 9, 10]. HTLV-1, like other retroviruses, contains the structural and enzymatic genes gag, pro, pol, and env flanked by 2 long terminal repeats (LTR). In addition, HTLV-1 encodes accessory and regulatory proteins in 4 open reading frames (ORFs) I–IV located at the 3′ end of the genome. ORFs III and IV encode 2 well-characterized genes, tax and rex. Tax appears to play an important role in HTLV-1 pathogenesis; it is the first viral protein detected in HTLV-1-expressing cells [11] and has been shown to be the immunodominant antigen recognized by cytotoxic T-lymphocytes (CTL) of patients with HAM and of ACs [12–16]. Recently a new viral protein, HTLV-1 basic leucine zipper (HBZ), has been identified; it is encoded by an ORF located between the env and tax/rex genes on the minus, or antisense, strand of the HTLV-1 provirus [17]. Transcription of HBZ is controlled by a promoter in the 3′ LTR. HBZ contains a transcription activation domain at the N-terminus and a leucine zipper at the C-terminus and the transcribed RNA has been shown to exist in 3 forms, unspliced HBZ (unHBZ), HBZ spliced-1 (HBZ-SP1), and HBZ spliced-2 (HBZ-SP2) [18, 19]. Unspliced HBZ and HBZ-SP1 have been studied the most, both forms have been detected in multiple HTLV-1 cell lines [18–21] and in peripheral blood mononuclear cells (PBMCs) isolated from patients with ATLL or HAM and from ACs [19–21]. HBZ appears to have biologically important activities at both the RNA and protein levels. HBZ protein inhibits Tax-mediated transactivation of viral transcription from the 5′ LTR through an interaction with JUN and ATF/CREB families [22–25]. HBZ RNA reportedly promotes T cell proliferation [19]. In transgenic mice HBZ promotes CD4+ T cell proliferation, while in inoculated rabbits HBZ enhances infectivity and persistence of HTLV-1 [26]. Similar genes encoded on the antisense strand of HTLV-2, HTLV-3 and HTLV-4 have been described [27–29]. The antisense transcript of HTLV-2 encodes the antisense protein APH-2 that remains able to bind to CREB and to down-regulate Tax-2 dependent expression although APH-2 lacks a leucine zipper domain [28]. We describe the use of an immunological assay to detect evidence of HBZ protein expression in vivo in patients with HAM and in ACs, and report a significant association between the detection of HBZ-specific CD8+ T cell responses with low viral load (LVL) and asymptomatic carriage of HTLV-1. These results are consistent with the conclusion of our recent study of class I binding of HTLV-1 epitopes [30], that the HLA class 1–restricted T cell response plays an important part in limiting HTLV-1 viral load and the risk of HAM.

Purpose Human T-cell lymphotropic virus type-I–associated adult T-cell leukemia/lymphoma (ATL) is an aggressive, chemotherapy-resistant malignancy. Multiple small studies using zidovudine (AZT) and interferon-alfa (IFN-α) have shown response in patients with ATL. However, the impact of this innovative antiviral treatment strategy on long-term survival remains undetermined. Patients and Methods We report a meta-analysis of antiviral therapy of ATL. Medical records of 254 patients with ATL who were treated in the United States, the United Kingdom, Martinique, and continental France were individually reviewed. Results According to Shimoyama classification, there were 116 patients with acute ATL, 18 patients with chronic ATL, 11 patients with smoldering ATL, and 100 patients with ATL lymphoma. In 231 patients with available survival data, first-line therapy was recorded in 207 patients. Five-year overall survival rates were 46% for 75 patients who received first-line antiviral therapy (P = .004), 20% for 77 patients who received first-line chemotherapy, and 12% for 55 patients who received first-line chemotherapy followed by antiviral therapy. Patients with acute, chronic, and smoldering ATL significantly benefited from first-line antiviral therapy, whereas patients with ATL lymphoma experienced a better outcome with chemotherapy. In acute ATL, achievement of complete remission with antiviral therapy resulted in 82% 5-year survival. Antiviral therapy in chronic and smoldering ATL resulted in 100% 5-year survival. Multivariate analysis confirmed that first-line antiviral therapy significantly improves overall survival of patients with ATL (hazard ratio, 0.47; 95% CI, 0.27 to 0.83; P = .021). Conclusion These results confirm the high efficacy of AZT and IFN, which should now be considered the gold standard first-line therapy in leukemic subtypes of ATL.

Objective The aim of the study was to describe pregnancies in HIV-infected teenagers. Methods A review of the case notes of HIV-infected pregnant teenagers aged 13–19 years from 12 London hospitals was carried out for the period 2000–2007. Results There were 67 pregnancies in 58 young women, of whom one was known to have acquired HIV vertically. The overall mother-to-child transmission (MTCT) rate of HIV was 1.5% (one of 66). There were 66 live births. Median ages at HIV diagnosis and conception were 17 and 18 years, respectively. Sixty-three per cent of women were diagnosed with HIV infection through routine antenatal screening. Eighty-two per cent of pregnancies (41 of 50) were unplanned, with 65% of women (26 of 40) using no contraception. Forty-three per cent of the women (20 of 46) had a past history of a sexually transmitted infection (STI). In 63 pregnancies, antiretroviral therapy was started post-conception, with prevention of HIV MTCT the only indication in 81% of cases. Fifty-eight per cent of those on highly active antiretroviral therapy (HAART) had an undetectable HIV viral load by delivery. Eighty-seven per cent were uncomplicated pregnancies. Seventy-one per cent delivered by Caesarean section and 21% (14 of 64) had a preterm delivery (

Undifferentiated nasopharyngeal carcinoma (NPC) is a geographically skewed disease in which more than 80% cases are from southern China and Southeast Asia. NPC is consistently associated with Epstein-Barr virus (EBV) infection and characterized by a prominent lymphocyte infiltration. The consistent expression of EBV proteins in NPC cells has led to several clinical trials of adoptive T-cell therapy or vaccination to boost the immune response to EBV antigens. However, these treatments yield relatively modest clinical benefit, which may be due to varying degrees of immunosuppression in the tumor microenvironment. The lack of model systems to analyze the ability of therapeutically relevant T cells to recognize and kill NPC cells represents a fundamental limitation in our attempts to harness the immune system for clinical benefit. We used three NPC cell lines as targets in T-cell assays, together with a panel of established HLA-matched EBV-specific CD8 and CD4 T-cell clones. T-cell activity and killing were measured by IFN-γ ELISA and outgrowth assays, respectively. We demonstrate, for the first time, that NPC cells can be recognized and killed by EBV-specific T-cell clones in vitro, which suggests that tumor-derived factors inhibit such responses in vivo. These observations are consistent with the previous reported functional inactivation of EBV-specific cytotoxic T lymphocytes (CTL) in NPC patients. We hypothesized that EBV infection of NPC cells induces the secretion of immunosuppressive factors. The effect of conditioned media derived from an EBV-infected premalignant nasopharyngeal cell line, NP460htert, on T-cell activity was examined by treating several clones of EBV-specific CTLs in vitro. The conditioned media inhibited the secretion of IFN-γ from peptide-stimulated CTLs, indicating that secreted factors that could suppress CTL functions are induced following EBV infection in NP460htert cells. RNA sequencing analyses on NP460hTert and three NPC cell lines following EBV infection revealed a significant enrichment of genes whose proteins are located at extracellular region/matrix, including a number of immunomodulators. Our results suggest that EBV infection might induce the production of soluble molecules, which in turn suppress the antitumor T-cell responses. In conclusion, we have developed a system with which to study NPC-specific immune responses and shown that soluble factors induced by EBV infection can suppress T-cell activity. These model systems will be critical in the future to examine the effects of checkpoint inhibitors, secreted factors from cancer-associated fibroblasts or NPC cells upon T-cell activity, which will ultimately enhance the success of EBV-targeted immunotherapy strategies. Citation Format: Hui Min Lee, Tracey Haigh, George SW Tsao, Paul G. Murray, Graham Taylor, Ian C. Paterson, Lee Fah Yap. The contribution of Epstein-Barr virus to the impaired T-cell responses in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4694.

Human T-lymphotropic virus type 1 (HTLV-1) spreads directly between lymphocytes and other cells via a specialized cell-cell contact, termed the virological synapse. The formation of the virological synapse is accompanied by the orientation of the microtubule-organizing center (MTOC) in the infected T cell toward the cell contact region with the noninfected target cell. We previously demonstrated that the combination of intracellular Tax protein expression and the stimulation of the intercellular adhesion molecule-1 (ICAM-1) on the cell surface is sufficient to trigger MTOC polarization in the HTLV-1–infected T cell. However, the mechanism by which Tax and ICAM-1 cause the MTOC polarization is not fully understood. Here we show that the presence of Tax at the MTOC region and its ability to stimulate cyclic AMP-binding protein–dependent pathways are both required for MTOC polarization in the HTLV-1–infected T cell at the virological synapse. Furthermore, we show that the MTOC polarization induced by ICAM-1 engagement depends on activation of the Ras-MEK-ERK signaling pathway. Our findings indicate that efficient MTOC polarization at the virological synapse requires Tax-mediated stimulation of T-cell activation pathways in synergy with ICAM-1 cross-linking. The results also reveal differences in the signaling pathways used to trigger MTOC polarization between the immunologic synapse and the virological synapse.

HTLV-1 is a significant global health problem but remains largely confined to endemic areas and risk groups. However, increasing migration may mean that the virus will be encountered more frequently in areas traditionally thought of as virtually free of HTLV-1. In this review we discuss the epidemiology, transmission, clinical features, diagnosis and treatment of HTLV-1, focussing specifically on the neurological manifestations. We highlight the circumstances in which HTLV-1 should be suspected and outline the current understanding of HTLV-1-associated myelopathy and other neurological presentations.

Evidence from population genetics, gene expression microarrays, and assays of ex vivo T-cell function indicates that the cytotoxic T lymphocyte (CTL) response to human T-lymphotropic virus type 1 (HTLV-1) controls the level of HTLV-1 expression and the proviral load. The rate at which CTLs kill autologous HTLV-1–infected lymphocytes differs significantly among infected people, but the reasons for such variation are unknown. Here, we demonstrate a strong negative cor-relation between the frequency of CD4+FoxP3+ Tax− regulatory T cells (Tregs) in the circulation and the rate of CTL-mediated lysis of autologous HTLV-1–infected cells ex vivo. We propose that the frequency of CD4+FoxP3+ Tax− Tregs is one of the chief determinants of the efficiency of T cell–mediated immune control of HTLV-1.

Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia, stimulates the growth of infected T cells in cultures and in nonleukemic patients. In the latter, HTLV-1 is found in long-term persisting T-cell clones. The persistence of normal T cells is controlled by the growth-stimulating and antiapoptotic functions of costimulatory receptors, while the growth-stimulating HTLV-1 functions are mediated by the viral oncoprotein Tax. Here we analyzed the impact of Tax on costimulatory receptors in T cells with repressible Tax and found that among these receptors 4-1BB (TNFRSF9/CD137/ILA) was induced most strongly. Up-regulated 4-1BB expression was a consistent feature of all HTLV-1–infected cell lines, whether patient-derived or in vitro transformed. Tax was sufficient to induce the expression of the endogenous 4-1BB gene in uninfected T cells, and it strongly activated (45-fold) the 4-1BB promoter via a single NF-κB site. The ligand of 4-1BB was also found on transformed T-cell lines, opening up the possibility of autostimulation. Moreover, 4-1BB expression in patients' lymphocytes ex vivo correlated with Tax expression, strongly suggesting Tax-mediated 4-1BB activation in vivo. Thus, 4-1BB up-regulation by Tax could contribute to growth, survival, and clonal expansion of the infected cells during persistence and disease.

Objective: We investigated whether previous treatment interruptions are associated with a raised risk of viral rebound in individuals who have attained virological suppression.Methods: All patients achieving an undetectable viral load while on therapy were followed until viral rebound or the time of the last viral load. Poisson regression was used to describe the independent impact of treatment interruptions on rebound rates.Results: A total of 12 977 patients from the United Kingdom Collaborative HIV Cohort (UK CHIC) Study achieved a viral load of less than 50 copies/ml. These patients contributed a total of 37 314 person-years of follow-up. The overall rebound rate was 8.07 (7.78, 8.36) per 100 person-years. In adjusted analyses, rates of viral rebound were up to 64% higher (rate ratio 1.64; 1.43, 1.88) in those who had previously interrupted therapy compared with those who had not. Patients who had interrupted at detectable viral loads had upto a 74% (1.74; 1.42, 2.14) higher chance of rebounding compared with those who had not interrupted with a detectable viral load. We found no evidence to suggest interrupting treatment at an undetectable viral load was associated with viral rebound.Conclusion: Among patients with an undetectable viral load, having previously interrupted therapy while the viral load was detectable is associated with a raised risk of rebound. (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.

It remains controversial whether in human immunodeficiency virus (HIV)-positive pregnant women an increased rate of preterm delivery is associated with highly active antiretroviral therapy (HAART). Since 1995 the management and outcome of all HIV-infected pregnant women delivering at St. Mary's Hospital London have been prospectively documented. The prevalence of preterm delivery and the correlation between gestational age and type of antiretroviral therapy were sought: preterm delivery occurred in 14.2% of the 211 deliveries. Initiation of HAART during pregnancy was associated with an increased risk of preterm delivery. This was independent of maternal health and class of antiretroviral therapy.

We investigated whether the rate of viral rebound decreases with increasing duration of viral suppression and, if so, whether rebound rates in patients previously failing antiretroviral regimens ultimately decline to levels as low as those seen in patients who have never experienced virological failure.All patients from the UK CHIC Study (n = 21 256) who achieved a viral load (VL) ofor = 50 copies/ml while receiving HAART were followed until viral rebound (two consecutive VL400 copies/ml). Patients could re-enter the analysis if they experienced a subsequent VLor = 50 copies/ml. Rebound rates were calculated according to the number of regimens previously failed and duration of viral suppression.Of 12 648 patients on HAART 10 237 (80.9%) achieved a VLor = 50 copies/ml. During 26 494 person-years (PY) of follow-up, 1853 (18.1%) patients experienced at least one viral rebound 'event', with 2460 events in total [rebound rate, 9.3 (range, 8.9-9.7)/100 PY). Within the first year of viral suppression, the rate of viral rebound was 8.3 (7.5-9.1)/100 PY in patients who had not previously failed treatment, increasing to 32.7 (27.6-37.8)/100 PY in patients who had failed more than four regimens. Irrespective of previous treatment failure, rebound rates in those who remained suppressed for4 years were similar to those in patients who had at no time experienced treatment failure.After around 4 years of viral suppression rebound rates in individuals with multiple prior treatment failures approach those of individuals with no prior treatment failure.

Background Nevirapine has been widely used in pregnancy for its efficacy, low pill burden, bioavailability and rapid transplacental transfer. Concern about nevirapine toxicity during pregnancy has emerged over recent years. Objectives The aims of the study were to document the frequency of cutaneous and hepatic toxicity secondary to nevirapine use during pregnancy and to compare rates in women starting nevirapine during the current pregnancy with those in women who had commenced nevirapine prior to the current pregnancy. Design This was a retrospective, comparative, five-centre study carried out in London, UK, in 1997–2003. Methods All HIV-1-infected women who received nevirapine as part of combination antiretroviral therapy (ART) during pregnancy were included in the study. Data on demographics, HIV infection risk, Centers for Disease Control and Prevention (CDC) status, surrogate markers at initiation of therapy, other medications hepatitis B and C virus coinfection and clinical data relating to potential toxicity were collated and analysed. Results Fifteen of 235 eligible women (6.4%) developed rash and eight (3.4%) developed hepatotoxicity, including four with coexistent rash, giving a combined incidence of 19 potential cases of nevirapine toxicity during pregnancy (8.1%). Alternative causes of rash/hepatotoxicity were suspected in seven cases and only 10 mothers (5.8%) discontinued nevirapine. Of the 170 women who commenced nevirapine during this pregnancy, 13 (7.6%) developed rash and eight (4.7%) hepatotoxicity, a combined incidence of 10%. Only two of 65 women with nevirapine exposure prior to this pregnancy developed rash (3.1%). Conclusions Nevirapine-containing ART was well tolerated in this cohort of pregnant women. Although pregnancy did not appear to increase the risk of nevirapine-associated toxicity compared to published adult data, CD4 count may be less predictive of toxicity in pregnancy.

Objective: The objective of this study is to assess the risk of viral rebound in postpartum women on suppressive combination antiretroviral therapy (cART). Methods: Using data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC), women with HIV-RNA 50 copies/ml or less at delivery in 2006–2011, who started life-long cART during pregnancy (n = 321) or conceived on cART (n = 618), were matched by age, duration on cART and time period, with at least one control (non-postpartum). The cumulative probability of viral rebound (HIV-RNA >200 copies/ml) was assessed by Kaplan–Meier analysis; adjusted hazard ratios (aHRs) for the 0–3 and 3–12 months postdelivery (cases)/pseudo-delivery (controls) were calculated in Cox proportional hazards models. Results: In postpartum women who conceived on cART, 5.9% [95% confidence interval (95% CI) 4.0–7.7] experienced viral rebound by 3 months, and 2.2% (1.4–3.0%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during the first 3 months [aHR 2.63 (1.58–4.39)] but not during the 3–12 months postdelivery/pseudo-delivery. In postpartum women who started cART during pregnancy, 27% (22–32%) experienced viral rebound by 3 months, and 3.0% (1.6–4.4%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during both postdelivery/pseudo-delivery periods [

Adult T cell leukaemia/lymphoma (ATL) is a predominantly CD4+ T cell neoplasia caused by human T cell lymphotropic Virus 1 (HTLV-1) infection. A few cases of CD8+ ATL have been reported but its existence has been debated. An Afrocaribbean female presented to the dermatology clinic with widespread papulo-nodular rash. HTLV-1 infection was detected by serology. Skin biopsy showed dense dermal infiltration by mainly CD8+ T cells which also expressed CD2, CD3, CD5, CD7 and occasionally CD25. Further investigations showed a mild lymphocytosis (4.4 x 106/L), circulating flower cells, absolute CD4+ count 1247 x 106/L (28.3% of lymphocytes), absolute CD8+ count x 2617 x 106/L (59.8% of lymphocytes), LDH 241 U/L (NR 135 – 214), Calcium 2.7 mmol/L (NR 2.2 – 2.6) but with increased serum PTH level. HTLV-1 proviral load (PVL) in peripheral blood mononuclear cells was 46%. PET/CT scan demonstrated FDG avid lymph nodes above and below the diaphragm. Axillary lymph node core biopsy showed CD20+ B cells nodules admixed with mainly small-to-medium sized T cells and a small population of large T cells. The small lymphocytes were mainly CD8+ T cells (also expressed CD2, CD3, CD5, and CD7 whereas the large cells expressed CD8, CD25 and CD30. Fewer than 5% expressed Ki67 (MIB-1). TCR clonality studies by PCR revealed expansion of an identical clone in all three compartments (skin, lymph node and blood). Detailed immunophenotyping on peripheral blood demonstrated a single dominant TCR vβ1+ clone (>90% of total CD8 T cells) which was CD3+, CD7+, CCR4+, CD25 low and, TSCL-1-. In summary we report a malignant CD8+ clone with atypical immunophenotype in a patient with high PVL. To confirm a working diagnosis of CD8+ ATL high throughput sequencing of each proviral integration sites is underway.

This is a study of the HTLV-1/HIV-1 co-infected cohort attending the National Centre for Human Retrovirology in London. In a retrospective analysis, demographic, clinical, immunological and virological data was described. A subgroup of patients on combination antiretroviral therapy (cART) for more than twelve months with an undetectable HIV viral load was identified and compared to a matched HTLV-1 mono-infected group. In an ongoing prospective study, HIV-1 mono-infected patients are recruited and virological and immunological parameters compared to the HTLV/HIV co-infected and HTLV mono-infected groups. 29 co-infected patients had a median age of 47 years, 55% were male and over 80% identified with the Black – African/Caribbean ethnic group. The median time on cART was 6 months. CD4/CD4% cell counts were lower in stable co-infected patients (508 cells/mm3, p=0.2 / 27.9%, p

Adult T cell leukemia (ATL) is typically characterised by expansion of a single dominant malignantly transformed HTLV-1-infected clone. Clinically, the abundance of this clone can be estimated by flow cytometric assessment of CD4, CD25 and CD7 expression, and, more recently, by quantitative LM-PCR analysis of viral integration site. In addition to the unique proviral integration site, malignant clones arising from a single infection event also share an identical T cell receptor (TCR) sequence, utilising one of a potential 47 TCR Vbeta subunit genes. Using multiparametric flow cytometry, we quantified the frequency of peripheral T cells bearing each of 24 TCR Vbeta subunits in a cohort of individuals with adult T cell leukemia or lymphoma (n=26) at various stages of disease progression/remission. To establish an appropriate baseline, we also analysed T cells from asymptomatic carriers (n=11) and donors with HAM/TSP (n=13). Vbeta-specific antibodies stained 75% of CD3+ cells in donors without malignancy, and the median size of the largest single subset (CD4+Vbeta2+) was 7.6 % of CD3+ cells. We detected putative T cell clones which exceeded 20% of CD3+ T cells only in individuals with active chronic or acute leukemia (n=17), reaching frequencies of up to 96% of CD3+ T cells. With this method, we quantified the expression on clonally expanded populations of the putative ATL cell markers CD25, CCR4, TSLC1, CD7 and CD127. Almost 1% of expanded clonal populations in ATL patients were CCR4+TSLC1+CD7–. Surprisingly, in most donors only 60% of the dominant clonal population expressed high levels of CD25. This flow cytometric protocol is a potentially powerful method to both monitor disease progression and response to therapy, providing fast and accurate quantification of clonally expanded populations. We are currently employing this technique to assay lysis of expanded clones by autologous cytotoxic T lymphocytes in patients with ATL.

Adult T cell leukaemia/lymphoma (ATL) is a highly heterogeneous neoplasm caused by human T cell lymphotropic virus type 1 (HTLV-1) infection. Shimoyama et al first proposed a prognostic classification based on clinical features. However subsequent studies have highlighted even greater heterogeneity and progression from indolent to aggressive subtypes. The molecular basis for this heterogeneity and progression remains unknown. Our aims were to identify molecular markers that characterize this heterogeneity and progression. We studied expression of T-cell markers and clonality (Ligation Mediated PCR) on peripheral blood mononuclear cells in samples collected from HTLV-1 infected patients (16 asymptomatic carrier [AC], 18 with HTLV-1-associated myelopathy [HAM], 18 with indolent ATL [five smouldering & 13 chronic] and seven with acute ATL) attending the National Centre for Human Retrovirology, London. 11/18 indolent ATL required no systemic treatment and one progressed to acute ATL. The remainder required systemic therapy and all except one achieved complete remission with zidovudine/interferon. 6/7 with acute ATL had primary refractory disease. Clonality testing showed no dominant clones in the AC, patient with HAM and 6 of the 11 patients with indolent ATL who didn't require systemic therapy. We confirmed CD4+CCR4+ as the main reservoir of HTLV-1 infection. These CD4+CCR4+ T cells had CD7+CD25+CD26+CD127+CCR7-immunophenotype in AC, HAM and indolent ATL with no dominant clones. CD7 down-regulation within CD4+CCR4+ T cells identified ATL patients with dominant clone(s). CD127 down-regulation within CD4+CCR4+ T cells was present in all indolent ATL patients which required systemic therapy. Nine patients with ATL (all acute and two indolent) had CCR7 up- regulation of which all but two had primary refractory disease. Longitudinal follow up in six patients showing changing immunophenotype which correlated with clinical features and prognosis. In conclusion CD7, CD127 and CCR7 expression within CD4+CCR4+ infected cells further characterises the heterogeneity within ATL with therapeutic implications.

The receptor for macrophage derived chemokine (MDC) and thymus- and activation-regulated chemokine (TARC) CC chemokine receptor 4 (CCR4) is over expressed in several T-cell malignancies including HTLV-1 related ATL where approximately 90% of malignant cells have been shown to over express this chemokine receptor. The HTLV-1 transactivator gene (Tax) does not directly induce CCR4 expression. Rather, expression of CCR4 is controlled by the constitutive activation of several transcription factors in HTLV-1 infected cells. Inhibiting the expression of these transcription factors with small-interfering RNAs has been shown to block CCR4 expression and also reduce proliferation of the affected cells. Patients with CCR4 positive ATL are more likely to have skin involvement and shorter overall survival (OS; median 9.5 months) compared with CCR4-negative (20.6 months) patients. Mogamulizumab is a defucosylated, humanized, monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (Potelligent®) against primary ATL cells that bind to CCR4.

Walking, a fundamental, complex, multifunctional task, is demanding of multiple body systems, interactively affecting walking capacity. Due to their restricted walking ability, activity and participation levels in patients with HTLV-1-Associated Myelopathy (pwHAM) are compromised. Primarily, the applicability of walking endurance using the 6 minute walk (6MW) and gait speed using the timed 10m walk (10mTW), in pwHAM, were explored. Distance covered, change over one year and the influence of pain were documented. Retrospectively, case notes were abstracted for gait (6MW; 10mTW) and pain, for all pwHAM, walking a minimum of 10m, at least 11 months apart. 26 pwHAM, (8-; 18-) met the assessment criteria. Mean age 58.5 years and disease duration was 10.46years ±6.02years. Observed distance walked (55m at T1 and 71m at T2) was shorter (p

HTLV-1 Tax protein is usually undetectable in freshly isolated peripheral blood mononuclear cells (PBMCs). After in vitro culture, the provirus is reactivated and Tax protein is detectable only in a proportion of infected CD4+ T cells: the percentage of Tax+ cells is always lower than the proviral load (PVL). To identify and further analyse the latently infected cells we have measured the expression of tumour suppressor of lung cancer 1 (TSLC1). TSLC1 is a member of the immunoglobulin super family that is expressed on all cells with the exception of PBMCs. It mediates cell-to-cell adhesion by either homophilic or heterophilic interactions with other members of the immunoglobulin family and also signals to the actin cytoskeleton. TSLC1 has been shown to be expressed on primary adult T cell leukaemia (ATL) cells and ATL cell lines. We assayed the expression of TSLC1 in the PBMCs of 13 asymptomatic carriers (AC) and 13 HAM/TSP patients by flow cytometry. We found that the percentage of TSLC1+ CD4+ T cells was positively correlated with the PVL (P < 0.0001). To test whether TSLC1+ cells themselves were infected, we flow sorted TSLC1+ CD4+ T cells of 3 ACs and 3 HAM/TSP patients. A median of 95% of TSLC1+ CD4+ T cells carried the provirus. Whilst only 20% of infected CD4+ T cells expressed Tax, a further 47% were identified on the basis of TSLC1 expression. As the host cytotoxic T cell (CTL) response is an important protective factor, we are now testing the hypothesis that the presence of TSLC1 on the surface of infected cells affects its recognition and subsequent killing by CTLs.

Background Human T-lymphotropic Virus Type I (HTLV-1) is a retrovirus that persistently infects 5–10 million individuals worldwide and causes disabling or fatal inflammatory and malignant diseases. The majority of the HTLV-1 proviral load is found in CD4+ T cells, and the phenotype of adult T cell leukemia (ATL) is typically CD4+. HTLV-1 also infects CD8+ cells in vivo, but the relative abundance and clonal composition of the two infected subpopulations have not been studied. We used a high-throughput DNA sequencing protocol to map and quantify HTLV-1 proviral integration sites in separated populations of CD4+ cells, CD8+ cells and unsorted peripheral blood mononuclear cells from 12 HTLV-1-infected individuals. Results We show that the infected CD8+ cells constitute a median of 5 % of the HTLV-1 proviral load. However, HTLV-1-infected CD8+ clones undergo much greater oligoclonal proliferation than the infected CD4+ clones in infected individuals, regardless of disease manifestation. The CD8+ clones are over-represented among the most abundant clones in the blood and are redetected even after several years. Conclusions We conclude that although they make up only 5 % of the proviral load, the HTLV-1-infected CD8+ T-cells make a major impact on the clonal composition of HTLV-1-infected cells in the blood. The greater degree of oligoclonal expansion observed in the infected CD8+ T cells, contrasts with the CD4+ phenotype of ATL; cases of CD8+ adult T-cell leukaemia/lymphoma are rare. This work is consistent with growing evidence that oligoclonal expansion of HTLV-1-infected cells is not sufficient for malignant transformation. Electronic supplementary material The online version of this article (doi:10.1186/s12977-015-0221-1) contains supplementary material, which is available to authorized users.

Nat. Rev. Dis. Primers article number: 15012; doi:10.1038/nrdp.2015.12; published online 18 June 2015 Figure 7 has been updated to clarify the treatment for patients with progressive disease.

(See the Major Article by Tanajura et al on pages 49–56.) The human T-cell lymphotropic virus type 1 (HTLV-1) is an oncogenic retrovirus that is transmitted from mother to child, particularly through prolonged breastfeeding; between sexual partners through unprotected intercourse; and from donors to recipients through transfusion and transplantation. Thirty-five years after its discovery, screening for HTLV-1 infection is at best patchy and mostly nonexistent. There are 2 main reasons for this: first, the most recent estimate of the prevalence of HTLV-1 is 5–10 million persons worldwide, with the important caveat that 86% of the global population is data poor in this regard [1]; second, there is a perception that disease related to this virus, which has coexisted with humankind for 60 000 years, is uncommon. Whether this reputation is justified requires up-to-date and reliable sero- and clinical epidemiology. The lifetime risk, among carriers, of adult-T-cell leukemia/lymphoma is 2%–6% regardless of the region of study. However, for HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP), more varied risks are reported with strong hints that, apart from the route of infection, ethnicity and human leukocyte antigen (HLA) types impact significantly on risk. Furthermore, HTLV-1 has been associated with a range of other inflammatory manifestations affecting many organs but particularly eyes, lungs, and thyroid and with increased susceptibility to a number of infections, most notably Strongyloides stercoralis hyperinfestation syndrome. (Given the high mortality of this latter condition, it is our policy to screen all HTLV-1 carriers who have resided in endemic areas for S. stercoralis). These diseases are much less well recognized even than HAM/TSP, with no data on incidence or prevalence among carriers. How, then, are we to judge the global disease burden of HTLV-1 infection? In this edition of Clinical Infectious Diseases, Tanajura et al report on a longitudinal study of 414 HTLV-1–infected individuals in Brazil [2]. There are a number of striking findings. First, among study participants not previously diagnosed with HAM/TSP, 18.4% had, at baseline assessment, symptoms, signs, and investigations consistent with a definite diagnosis of HAM/TSP. Second, an additional 21%, again at baseline, had possible or probable HAM/TSP on the basis of having either 1 motor sign consistent with HAM/TSP or a neurogenic bladder (probable) or a clinical diagnosis of HAM/TSP without exclusion of other possible diagnoses (possible). Third, during up to 8 years of follow-up, 5 subjects (all from the probable HAM/TSP category) were diagnosed with definite HAM, an incidence of 1.5%. Finally, very high incidences of a range of neurological symptoms were documented, particularly sensory, including upper limb, even though the median per-person follow-up was only 2 years. These findings are notable because they differ by an order of magnitude from most previous reports. Using data from the mid-1980s, Kaplan et al estimated a 0.25% lifetime risk of HAM in HTLV-1–infected Japanese individuals, based on an average of 24.3 new cases reported per year among approximately 794 800 seropositive individuals (3/100 000 cases per annum) [3]. These data have undoubtedly affected some public health decisions outside Japan. However, in the Caribbean, Murphy et al diagnosed myelopathy in 0.5% of HTLV-1 carriers in a case-control study [4], whereas Maloney et al estimated the lifetime risk of HAM/TSP at 1.9% with an age-standardized annual incidence of 17.3 per 100 000 infected males and 24.7 per 100 000 infected females [5]. In the United States, Murphy et al diagnosed myelopathy in 2.4% (4/166) newly diagnosed HTLV-1–infected blood donors [6]; importantly, this study included matched uninfected controls. Although there is an extensive literature on the influence of HLA types on risk of disease associated with HTLV-1 infection, especially through impact on proviral load, and further evidence of ethnic differences based on rates of HAM/TSP according to tribe in a small study from Zaire [7], the cross-sectional prevalence reported from Brazil suggests a lifetime risk in this population 10-fold higher than previously reported. Is this due to genetics or environment or selection bias? The risk of HAM/TSP has been strongly associated with proviral load and, in particular, with a cutoff of 1 HTLV-1 DNA copy per 100 peripheral blood mononuclear cells (a proviral load of 1%) [8]. The Miyazaki Cohort Study followed almost 2000 persons, among whom 27% were HTLV-1 infected, in a decade-long study and reported paraesthesia, polyuria, and nocturia to be twice as common among those infected with HTLV-1. However, finding no association with HTLV-1 proviral load or strength of antibody response, they concluded that HTLV-1 per se was not causatively associated [9]. Similarly, Tanajura et al found no association with the frequency of sensory, bladder, or even motor symptoms and HTLV-1 proviral load even though up to 30% of the study participants developed such symptoms during follow-up. They did find, however, that carriers with HTLV-1 proviral loads of >5% were more likely to have demonstrated deterioration in expanded disability status score. Also at baseline, subjects diagnosed with HAM/TSP had higher median HTLV-1 proviral load (14.8%) than those who were initially asymptomatic (2.5%), with the probable/possible HAM/TSP subset intermediate at 4%. It seems, therefore, that the proviral load in this cohort may be higher than in other cohorts that cite a median of 1% for asymptomatic carriers. Even so, this does not fully account for the exceptionally high prevalence and incidence of definite HAM/TSP as assuming a lifetime risk of HAM/TSP of up to 3%, even subjects with proviral loads >1% have only a 6% lifetime risk. Because only 59% of the cohort was identified through screening, with 32% self-referred and the remainder identified by the neurology service or by having HTLV-1 in the family, further breakdown of the data from the blood donors only would be more comparable with other studies and potentially contribute to understanding the role, if any, of selection bias. In particular, the high rate of sensory symptoms of the upper limbs are difficult to explain from previous reports of HAM/TSP and raise various possibilities, including overreporting by study participants and the presence of additional factors or alternative etiologies. It is difficult to comment on the contribution of environment (clinic and community), but there is now an urgent need to test these findings in a new study with HTLV-1–uninfected matched controls. If confirmed, at least in some infected communities, the disease burden of HTLV-1 is considerably higher than previously reported, and this should stimulate broader and more effective prevention programs and greater interest and financial support for research into the treatment of HAM/TSP.

Human T-cell lymphotropic virus-I (HTLV-I) is the cause of adult T-cell leukaemia/lymphoma. Various viral proteins, especially, but not exclusively, Tax have been implicated in oncogenesis, mostly through in vitro studies. Tax transactivates a large and apparently ever expanding list of human genes through transcriptional factors. Elucidating not only the pathways but also the timing of action of HTLV proteins is important for understanding the pathogenesis and development of new treatments.

The dynamics of human T-lymphotropic virus type-1 (HTLV-1) provirus expression in vivo are unknown. There is much evidence to suggest that HTLV-1 gene expression is restricted: this restricted gene expression may contribute to HTLV-1 persistence by limiting the ability of the HTLV-1–specific CD8+ cell immune response to clear infected cells. In this study, we tested the hypothesis that derepression of HTLV-1 gene expression would allow an increase in CD8+ cell–mediated lysis of HTLV-1–infected cells. Using histone deacetylase enzyme inhibitors (HDIs) to hyperacetylate histones and increase HTLV-1 gene expression, we found that HDIs doubled Tax expression in naturally infected lymphocytes after overnight culture. However, the rate of CD8+ cell–mediated lysis of Tax-expressing cells ex vivo was halved. HDIs appeared to inhibit the CD8+ cell–mediated lytic process itself, indicating a role for the microtubule-associated HDAC6 enzyme. These observations indicate that HDIs may reduce the efficiency of cytotoxic T-cell (CTL) surveillance of HTLV-1 in vivo. The impact of HDIs on HTLV-1 proviral load in vivo cannot be accurately predicted because of the widespread effects of these drugs on cellular processes; we therefore recommend caution in the use of HDIs in nonmalignant cases of HTLV-1 infection.

OBJECTIVES: To document postpartum disease-free survival of HIV-infected women taking antiretroviral therapy (ART) during pregnancy. METHODS: Laboratory and clinical data were collected on all HIV-infected pregnant women delivering from 1998 to 2002 and followed up until September 2004 at 6 hospitals in London. Mothers were grouped according to receipt of zidovudine monotherapy (ZDVm), highly active antiretroviral therapy (HAART) given during and continued after pregnancy (cHAART), and short-term HAART given during pregnancy and discontinued on delivery (START). RESULTS: Eight-five women took ZDVm, 155 took cHAART, and 71 took START. The mean follow-up for all mothers was 33 months, with a total of 847 person-years. At the first antenatal clinic (ANC) visit, 72% of women were in Centers for Disease Control and Prevention (CDC) stage A, 85% were treatment naive, and the ZDVm group had a median HIV viral load (VL) 10-fold less than those mothers who started HAART during pregnancy. At last follow-up, 1 patient had died and 6 (1.9%) had progressed to CDC stage C; 62% of all women, including a quarter of the ZDVm group, were receiving HAART for their own health; and 83% of all mothers had a VL

After cell-to-cell transmission, HTLV-I increases its viral genome by de novo infection and proliferation of infected cells. Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected cells are selected in vivo by the host's immune system, the genetic and epigenetic environment of proviral integration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired by genetic and epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the host immune system. On the other hand, ATL cells acquire the ability to proliferate without Tax by intracellular genetic and epigenetic changes. Despite advances in support and the development of novel treatment agents, the prognosis for ATLL remains poor. A number of therapies, however, do appear to improve prognosis compared to CHOP (VEPA). These include interferon-alpha plus zidovudine (probably after 1-2 cycles of CHOP), intensive chemotherapy as in LSG-15 with G-CSF support and Allo-SCT (which includes the potential for cure). Emerging novel approaches include HDAC inhibitors, monoclonal antibodies, and proteasome inhibitors. Comparison between different therapeutic approaches is complicated by the range of natural history of ATLL, different recruitments of naïve-to-therapy, refractory or relapsed patients, and variations in the reporting of outcome that frequently excludes difficult-to-evaluate patients. Moreover, results from relatively small proof-of-principle studies have not been extended with randomized, controlled trials. As a result, currently, there is no clear evidence to support the value of any particular treatment approach over others. To avoid further unnecessary patient suffering and to identify optimal therapy as rapidly as possible, large randomized, controlled trials encompassing multicenter, international collaborations will be necessary.

Cell-cell contact is required for efficient transmission of human T-lymphotropic virus type 1 (HTLV-1). An HTLV-1–infected cell polarizes its microtubule-organizing center (MTOC) toward the cell-cell junction; HTLV-1 core (Gag) complexes and the HTLV-1 genome accumulate at the point of contact and are then transferred to the uninfected cell. However, the mechanisms involved in this cytoskeletal polarization and transport of HTLV-1 complexes are unknown. Here, we tested the hypothesis that engagement of a specific T-cell surface ligand is synergistic with HTLV-1 infection in causing polarization of the MTOC to the cell contact region. We show that antibodies to intercellular adhesion molecule-1 (ICAM-1; CD54) caused MTOC polarization at a higher frequency in HTLV-1–infected cells. ICAM-1 is upregulated on HTLV-1–infected cells, and, in turn, ICAM-1 on the cell surface upregulates HTLV-1 gene expression. We propose that a positive feedback loop involving ICAM-1 and HTLV-1 Tax protein facilitates the formation of the virologic synapse and contributes to the T-cell tropism of HTLV-1. In contrast, MTOC polarization induced in T cells by antibodies to CD3 or CD28 was significantly inhibited by HTLV-1 infection.

BACKGROUND: Up to 20 million persons are infected with the human retroviruses human T-lymphotropic virus (HTLV)-I and HTLV-II globally. Most data on the seroprevalence of HTLV-I and HTLV-II in Europe are from studies of low-risk blood donors or high-risk injection drug users (IDUs). Little is known about the general population. METHODS: A prospective anonymous study of HTLV-I and HTLV-II seroprevalence among 234,078 pregnant women in Belgium, France, Germany, Italy, Portugal, Spain, and the United Kingdom was conducted. Maternal antibody status was determined by standard methods using sera obtained for routine antenatal infection screens or eluted from infant heel prick dried blood spots obtained for routine neonatal metabolic screens. RESULTS: Anti-HTLV-I/II antibodies were detected and confirmed in 96 pregnant women (4.4 per 10,000, 95% confidence interval [CI]: 3.5-5.2). Of these, 73 were anti-HTLV-I, 17 were anti-HTLV-II, and 6 were specifically anti-HTLV but untyped. The seroprevalence ranged from 0.7 per 10,000 in Germany to 11.5 per 10,000 in France. CONCLUSIONS: Pregnant women better reflect the general population than blood donors or IDUs. The seroprevalence of HTLV-I and HTLV-II in Western Europe is 6-fold higher among pregnant women (4.4 per 10,000) than among blood donors (0.07 per 10,000). These data provide a robust baseline against which changes in HTLV-I and HTLV-II seroprevalence in Europe can be measured.

The geographic distribution of Human T-cell Lymphotropic Virus Type 1 (HTLV-1) infection makes one thing clear: except Japan, most of the estimated 20 million infected individuals are clustered within communities with limited health care access [1]. Given that the majority of infected persons remain disease-free, one of the challenges of the clinical management of HTLV-1-infected patients with myelopathic symptoms is to establish the definite diagnosis of HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Asymptomatic carriers may complain of a range of symptoms that cannot be excluded from an association with HTLV-1, such as dry eyes, urinary incontinence and constipation. Current HAM/TSP diagnostic procedures are based on criteria established by the World Health Organization (WHO), which consists of a list of neurological signs and symptoms in HTLV-1 seropositive subjects. In addition, imaging of the central nervous system is essential to exclude other neurological diseases with similar clinical features, whilst isolation of HTLV-1 proviral in the cerebrospinal fluid (CSF) [2] is a positive finding, especially when the viral load in CSF lymphocytes is greater than in PBMCs [3]. However, these complementary tests are not readily available in many communities. In our experience, patients rarely present with all the essential features of HAM/TSP to meet the diagnostic requirements of the complete syndrome. To complement WHO criteria, a new classification strategy, the Belem Criteria, based on three diagnostic ascertainment levels was proposed [4]. HTLV-1-infected patients with neurological defects are categorized as: (i) Definite HAM/TSP: patients who meet the established WHO criteria with a complete clinical presentation; (ii) Probable HAM/TSP: patients with a myelopathic mono-symptomatic presentation, in which other diseases resembling HAM/TSP have been excluded; (iii) Possible HAM/TSP: patients who present with a complete or incomplete clinical picture; however, other disorders resembling HAM/TSP cannot be excluded. In recent years, several studies have demonstrated a clear association between HAM/TSP and HTLV-1 proviral load [5-11]. Moreover, compelling evidence indicates that patients with other HTLV-1-associated inflammatory conditions, such as infective dermatitis [12] or keratoconjunctivitis sicca [13], display significantly higher levels of proviral load compared to asymptomatic carriers. In a published study conducted in Bahia, Brazil, we found that a proviral load cut-off value of 50,000 copies/106 PBMCs (5%), differentiated asymptomatic carriers from HAM/TSP patients with 87% sensitivity and 81% specificity [14]. Using the Belem criteria, only 22% of probable and 17% of definite HAM/TSP patients’ HTLV-1 proviral loads fell below this cut-off value. If this threshold had been included as an additional criterion to diagnose HAM/TSP, 73% of patients from the probable group would be reclassified as definite. Furtado et al. [15] also attempted to establish a proviral load cut-off value to distinguish asymptomatic carriers from HAM/TSP patients in Minas Gerais (Brazil). Using whole blood, a cut-off of 114 HTLV-1 copies/104 white blood cells (1.14%), offered 78.2% sensitivity and 28% specificity in patients with HAM/TSP. This value is considerably lower than what was observed in Bahia. As members of the HAM/TSP Clinical Trial Study Group (HAM/TSP-CTSG) we performed a literature review of proviral loads reported in asymptomatic carriers and HAM/TSP patients (Table 1). The percentage of infected cells was approximately 6× higher in HAM/TSP patients (median 6.8%, 5.4–18%) than in asymptomatic carriers (median 1.1%, 0.3–5.6%). Despite overlapping ranges, the trends are consistent across studies. However, study groups used diverse methods to measure proviral load, including different regions of the targeted HTLV-1 genome, the DNA sample source, e.g. whole blood cells or isolated PBMCs and cells quantified from patient samples. In personal consultation with HAM/TSP CTSG members we established that 7.04% and 10% of patients with definite HAM/TSP, living in Bahia, Brazil and Japan respectively, have a proviral load of 1% [3]. Based on the reviewed data and our own observations across four centres (Bahia/Japan/UK/USA) a single cut-off for asymptomatic versus HAM/TSP or for definite versus probable HAM/TSP cannot be recommended. Table 1 Methodological characteristics of HTLV-1 proviral load measurements using PCR method from asymptomatic carriers and HAM/TSP patients in endemic countries for HTLV-1-infection. We therefore propose an international pilot study in an attempt to achieve consistent results in order to evaluate HTLV-1 proviral load in PBMCs of asymptomatic carriers as well as patients with probable, possible and definite HAM/TSP living in HTLV-1 endemic and non-endemic areas. By testing these patients at several chosen established laboratories blinded to samples’ origins, we hope to take initial steps towards the standardization of proviral load quantification technique, with the ultimate goal of determining a relevant proviral load cutoff value to distinguish asymptomatic carriers from HAM/TSP patients. At the same time, we recognize that, due to variation from assay to assay, there are limitations with respect to viral load quantification [16,17]. In the future, the HTLV research community might propose the incorporation of a WHO international standard to aid in clinical applications by soliciting assistance from such groups as Standardization of Genome Amplification Techniques or National Institute for Biological Standards and Control.

Aims: The epidemiological and pathological features of Hodgkin lymphoma (HL) are complex. The Epstein-Barr virus (EBV) is consistently associated with a proportion of cases, and these cases are thought to represent a distinct aetiological subgroup of HL. The aim of the present analysis was to determine the age and sex specific incidence of EBV associated and non-associated HL, analysed separately, using data derived from a population based study–the Scotland and Newcastle epidemiological study of Hodgkin’s disease (SNEHD). This study also provided a unique opportunity to evaluate accuracy in the current diagnosis and classification of HL. Methods: SNEHD analysed consecutive cases of HL diagnosed in the study area between 1993 and 1997. Diagnostic biopsy material was retrieved, EBV status of tumours was determined, and histological review was performed. Results: In total, 622 cases were eligible for the study, and EBV studies and histopathological review were performed on biopsy material from 537 and 549 cases, respectively. Accuracy in the overall diagnosis of HL and classification of nodular sclerosis HL was good, but diagnosis of HL in the elderly and classification of other subtypes was less reliable. One third of classic HL cases were EBV associated, and age specific incidence curves for EBV associated and non-associated cases were distinct. Conclusions: Comparison of age specific incidence curves for EBV associated and non-associated HL supports the hypothesis that these are two distinct aetiological entities. Accuracy in the diagnosis of HL is generally good, but certain subgroups of cases continue to present diagnostic difficulties.

HTLV infection appears to be more common among renal transplant candidates than in the related general population. HTLV-1-associated diseases may occur in carriers who are transplanted but there is insufficient evidence to confirm whether these occur more frequently as a result of the associated immunosuppression. Consequently, pre-existing HTLV-1 infection should not be considered a contra-indication to transplantation. The risk of transmission of HTLV-1 through solid organ transplantation from a confirmed infected donor is unknown. There are anecdotes of multiple infections from a single donor. Biologically due to the significant volume of blood and the lack of storage, transmission would be expected to be higher than following blood transfusion. The rate of subsequent disease is unknown, but there are now 11 reports of HAM and 2 of ATL occurring within 4 years of transplantation associated infection. There are insufficient data to know whether the time from infection to onset of disease and the rate of progression differ from transmission through other routes, but early onset and rapid progression is a concern. Responses to enhanced immunosuppression for the treatment of HAM are variable. The risk of HTLV-1 associated disease in exchange for a life-saving major organ transplantation from an infected donor might be considered worth taking by some HTLV-1 uninfected patients. Peri-transplantation antiretroviral prophylaxis with zidovudine and raltegravir is biologically sound but therapeutically unproven. The risks related to HTLV-1 infection appear to preclude the use of any other tissue. All transplant donors should be screened for HTLV-1 infection regardless of perceived risk.

CD4+ T cells are critical for inducing and maintaining efficient humoral and cellular immune responses to pathogens. The CD4+ T-cell response in human T-lymphotropic virus 1 (HTLV-1) infection has not been studied in detail. However, CD4+ T cells have been shown to predominate in early lesions in HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP). We present direct estimates of HTLV-1 Env- and Tax-specific CD4+ T-cell frequencies in patients infected with HTLV-1. We first showed that there was a strong bias toward the Th1 phenotype in these HTLV-1–specific CD4+ T cells in patients with HAM/TSP. We then demonstrated significantly higher frequencies of HTLV-1–specific Th1-type CD4+ T cells in HAM/TSP patients than in asymptomatic HTLV-1 carriers. The majority of these HTLV-1–specific CD4+ T cells did not express HTLV-1 Tax and were therefore unlikely to be infected by HTLV-1. High frequencies of activated HTLV-1–specific CD4+ T cells of the Th1 phenotype might contribute to the initiation or pathogenesis of HAM/TSP and other HTLV-1–associated inflammatory diseases.

Background: Salvador is the city with the highest number of HTLV-1 infected individuals in Brazil, yet the main route of HTLV-1 transmission is unknown. Objective: To investigate the association of syphilis infection as a proxy for sexual transmission of HTLV-1 infection in the general population of this city. Methods: A cross sectional population-based study was conducted with 3,451 serum samples obtained by a representative simple random sampling. Data on gender, age, income, and years of education were collected by questionnaire and the presence of HTLV, HIV and Treponema pallidum infection was determined by serology. Logistic regression analysis was used to evaluate the independent effect of the potential explanatory variables to HTLV-1 infection and Odds Ratios (OR) and 95% CI were calculated. Results: The majority of studied individuals were female (56.4%), had less than 7 years of education (55.3%) and earned two or less minimum wages (52.0%). The overall prevalence of HTLV-1 was 1.48% (51/3,451; 95% CI: 1.10%– 1.94%), which increased with age. Only three persons younger than 17 (3/958; 0.31%; CI 95% 0.06–0.91) years were infected by HTLV-1. Among the 45 syphilis positives, 12 (26.7%) were HTLV positive, while among 21 HIV positives, only one (4.8%) was HTLV positive. HTLV-1 infection was found to be associated with syphilis infection (ORADJUSTED 36.77; 95% CI 14.96–90.41). Conclusion: The data presented herein indicate that horizontal transmission between adults is the main route of HTLV-1 infection in the general population of Salvador and that this is likely to occur through sexual contact.

Objectives Macrolide resistant Treponema pallidum strains, caused by mutations in the 23S ribosomal RNA (23S rRNA) gene, are widespread and increasingly prevalent. The authors aimed to establish the strain types of T pallidum isolated from patients in a London sexual health centre and to determine the frequency of macrolide resistance. Methods T pallidum DNA from blood and ulcer samples were subjected to strain typing and mutation analysis using previously described methods. Results 18 samples were tested and a 23S rRNA point mutation conferring macrolide resistance was found in 66.6%. All resistant strains were collected from men who have sex with men and both the A2058G and the A2059G mutations were found. Two strain types were identified (14d/g and 14d/f); the predominant strain type was 14d/g and an association was noted between tp0548 type g and macrolide resistance. Conclusions High levels of T pallidum macrolide resistance are present in London, UK, and this has clear implications for national treatment guidelines.

The past 15 years have seen a dramatic increase in syphilis diagnoses in several regions including China, North America, Western Europe and Australia. Worldwide, the disease remains prevalent, contributing to substantial adult morbidity and neonatal mortality. Testing and treatment strategies are largely informed by data from the early antibiotic era, but increasing use of molecular diagnostics and new screening strategies could improve the management of syphilis substantially.The review explores new testing strategies for syphilis, including the importance of screening test selection and advances in point-of-care diagnostics. It then examines molecular studies of Treponema pallidum, covering typing; macrolide resistance; association between genotype and phenotype and the use of PCR in testing and monitoring strategies.Clinicians should be aware of testing strategies employed by their laboratories to ensure optimal sensitivity and specificity. Locally available T. pallidum PCR assays may improve the diagnosis of early disease and inform antibiotic choice. Robust serologic follow-up is still required, but predictors of potential treatment failure, including PCR-measured bacterial load, have been identified. Re-treatment should be considered for patients in the serofast state. The publication of T. pallidum genomes would allow further and more detailed study of strains and disease pathogenesis.

HIV-infected individuals with severe immunodeficiency are at risk of opportunistic infection (OI). Tuberculosis (TB) may occur without substantial immune suppression suggesting an early and sustained adverse impact of HIV on Mycobacterium tuberculosis (MTB)-specific cell mediated immunity (CMI). This prospective observational cohort study aimed to observe differences in OI-specific and MTB-specific CMI that might underlie this. Using polychromatic flow cytometry, we compared CD4+ responses to MTB, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Candida albicans in individuals with and without HIV infection. MTB-specific CD4+ T-cells were more polyfunctional than virus specific (CMV/EBV) CD4+ T-cells which predominantly secreted IFN-gamma (IFN-γ) only. There was a reduced frequency of IFN-γ and IL-2 (IL-2)-dual-MTB-specific cells in HIV-infected individuals, which was not apparent for the other pathogens. MTB-specific cells were less differentiated especially compared with CMV-specific cells. CD127 expression was relatively less frequent on MTB-specific cells in HIV co-infection. MTB-specific CD4+ T-cells PD-1 expression was infrequent in contrast to EBV-specific CD4+ T-cells. The variation in the inherent quality of these CD4+ T-cell responses and impact of HIV co-infection may contribute to the timing of co-infectious diseases in HIV infection.

Currently, the efficacy of syphilis treatment is measured with anti-lipid antibody tests. These can take months to indicate cure and, as a result, syphilis treatment trials require long periods of follow-up. The causative organism, Treponema pallidum (T. pallidum), is detectable in the infectious lesions of early syphilis using DNA amplification. Bacteraemia can likewise be identified, typically in more active disease. We hypothesise that bacterial clearance from blood and ulcers will predict early the standard serology-measured treatment response and have developed a qPCR assay that could monitor this clearance directly in patients with infectious syphilis. Patients with early syphilis were given an intramuscular dose of benzathine penicillin. To investigate the appropriate sampling timeframe samples of blood and ulcer exudate were collected intensively for T. pallidum DNA (tpp047 gene) and RNA (16S rRNA) quantification. Sampling ended when two consecutive PCRs were negative. Four males were recruited. The mean peak level of T. pallidum DNA was 1626 copies/ml whole blood and the mean clearance half-life was 5.7 hours (std. dev. 0.53). The mean peak of 16S rRNA was 8879 copies/ml whole blood with a clearance half-life of 3.9 hours (std. dev. 0.84). From an ulcer, pre-treatment, 67,400 T. pallidum DNA copies and 7.08x107 16S rRNA copies were detected per absorbance strip and the clearance half-lives were 3.2 and 4.1 hours, respectively. Overall, T. pallidum nucleic acids were not detected in any sample collected more than 56 hours (range 20–56) after treatment. All patients achieved serologic cure. In patients with active early syphilis, measuring T. pallidum levels in blood and ulcer exudate may be a useful measure of treatment success in therapeutic trials. These laboratory findings need confirmation on a larger scale and in patients receiving different therapies., Author Summary Syphilis is an infection that is spread both sexually and from mother-to-child. Worldwide, it affects an estimated 11 million people each year. Treatment is available, but relies heavily on penicillin and may not be as effective where the infection involves the brain or nervous system. Clinical trials are needed to assess new treatments, but proving that people are cured with current tests can take months. We developed a new test to measure the success of treatment for the early stage of syphilis. We then used it in four patients and found that the syphilis bacteria were cleared from the blood and ulcer samples collected by 56 hours. All four patients were followed up with normal tests and found to have been cured. Our new test is the first to show the speed of bacterial clearance after treatment and we plan to use it in clinical trials of new treatments. Our data may also mean that patients with syphilis are unable to pass on the infection three days after treatment, but this also needs proving on a larger scale.

Introduction.There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy.Methods.A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010.Results.There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), “preconception” atazanavir exposure; 27 started atazanavir-based cART as “first-line” during the pregnancy; and 29 “switched” to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (Conclusions.These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.

Although recombination is a major source of genetic variability in retroviruses, no recombinant strain had been observed for HTLV-1, the first isolated human-pathogenic retrovirus. Different genotypes exist for HTLV-1: Genotypes b and d to g are restricted to central Africa, while genotype c is only endemic in Australo-Melanesia. In contrast, the cosmopolitan genotype A is widely distributed. We applied a combination of phylogenetics and recombination analysis approaches to a set of new HTLV-1 sequences, including the complete LTR and a 522-bp fragment of the env gene, which we collected from 19 countries throughout North, West and Central Africa, the continent where the virus has the largest endemic presence. The samples were obtained from 41 HTLV-1 infected individuals with different clinical statuses including ATL, TSP/HAM and asymptomatic carriers. The recombinant search and breakpoint detection were performed by boot scanning in Simplot to compare inferred clusters of sequences to each other. Finally, molecular clock analyses were performed to date the recombinant event observed. This led us to demonstrate the presence of recombinants in HTLV-1. Indeed, the HTLV-1 strains currently present in North Africa have originated from a recombinant event between strains from Senegal and West Africa. This recombination is estimated to have occurred around 4,0 years ago. This recombination seems to have been generated during reverse transcription. In conclusion, we demonstrate that, albeit rare, recombination can occur in HTLV-1 and may play a role in the evolution of this retrovirus (Desrames et al., J. Virology, 88, 2014). In order to precise the geographical distribution of this recombinant within the African Continent, we studied a new set of samples from HTLV-1 infected patients of diverse African origin. The data on this on-going study will be presented.