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Graham P Taylor

Publications and source records attributed to Graham P Taylor.

At least 19 recordsLinked to original sources
PubMed2006

Pregnant women with HIV infection can expect healthy survival: three-year follow-up.

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 <50 HIV RNA copies/mL of plasma regardless of whether they were on treatment or not. CONCLUSIONS: The median-term postpartum prognosis of HIV-infected pregnant women with access to HAART is good. Exposure to short-course ZDVm or START during pregnancy did not jeopardize their response to subsequent therapy.

Adult↗
PubMed2006

Zidovudine plus lamivudine in Human T-Lymphotropic Virus type-I-associated myelopathy: a randomised trial.

BACKGROUND: No therapies have been proven to persistently improve the outcome of HTLV-I-associated myelopathy. Clinical benefit has been reported with zidovudine and with lamivudine in observational studies. We therefore conducted a randomised, double blind, placebo controlled study of six months combination therapy with these nucleoside analogues in sixteen patients. RESULTS: Primary outcomes were change in HTLV-I proviral load in PBMCs and clinical measures. Secondary endpoints were changes in T-cell subsets and markers of activation and proliferation. Six patients discontinued zidovudine. No significant changes in pain, bladder function, disability score, gait, proviral load or markers of T-cell activation or proliferation were seen between the two arms. Active therapy was associated with an unexplained decrease in CD8 and non-T lymphocyte counts. CONCLUSION: Failure to detect clinical improvement may have been due irreversible nerve damage in these patients with a long clinical history and future studies should target patients presenting earlier. The lack of virological effect but may reflect a lack of activity of these nucleoside analogues against HTLV-I RT in vivo, inadequate intracellular concentrations of the active moiety or the contribution of new cell infection to maintaining proviral load at this stage of infection may be relatively small masking the effects of RT inhibition.

Aged↗
PubMed2006

Histone deacetylase inhibitors increase virus gene expression but decrease CD8+ cell antiviral function in HTLV-1 infection.

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.

CD8-Positive T-Lymphocytes↗
PubMed2006

Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM).

After the first description of TSP/HAM in 1985 and the elaboration of WHO's diagnostic criteria in 1988, the experience of the professionals in this field has increased so that a critical reappraisal of these diagnostic guidelines was considered timely. Brazilian neurologists and observers from other countries met recently to discuss and propose a modified model for diagnosing TSP/HAM with levels of ascertainment as definite, probable, and possible, according to myelopathic symptoms, serological findings, and/or detection of HTLV-I DNA and exclusion of other disorders.

Adult↗
PubMed2005

Quantification of the virus-host interaction in human T lymphotropic virus I infection.

BACKGROUND: HTLV-I causes the disabling inflammatory disease HAM/TSP: there is no vaccine, no satisfactory treatment and no means of assessing the risk of disease or prognosis in infected people. Like many immunopathological diseases with a viral etiology the outcome of infection is thought to depend on the virus-host immunology interaction. However the dynamic virus-host interaction is complex and current models of HAM/TSP pathogenesis are conflicting. The CD8+ cell response is thought to be a determinant of both HTLV-I proviral load and disease status but its effects can obscure other factors. RESULTS: We show here that in the absence of CD8+ cells, CD4+ lymphocytes from HAM/TSP patients expressed HTLV-I protein significantly more readily than lymphocytes from asymptomatic carriers of similar proviral load (P = 0.017). A high rate of viral protein expression was significantly associated with a large increase in the prevalence of HAM/TSP (P = 0.031, 89% of cases correctly classified). Additionally, a high rate of Tax expression and a low CD8+ cell efficiency were independently significantly associated with a high proviral load (P = 0.005, P = 0.003 respectively). CONCLUSION: These results disentangle the complex relationship between immune surveillance, proviral load, inflammatory disease and viral protein expression and indicate that increased protein expression may play an important role in HAM/TSP pathogenesis. This has important implications for therapy since it suggests that interventions should aim to reduce Tax expression rather than proviral load per se.

Adult↗
PubMed2005

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy.

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.

Adult↗
PubMed2005

Human T-lymphotropic virus, type 1, tax protein triggers microtubule reorientation in the virological synapse.

We showed recently that the human T-lymphotropic virus, type 1 (HTLV-1), spreads directly from cell to cell via a virological synapse. The HTLV-1 virological synapse resembles the immunological synapse; each is a specialized contact between a lymphocyte and another cell that contains organized protein microdomains, and each involves repolarization of the T-cell microtubule cytoskeleton. However, formation of the virological synapse is not triggered by T-cell receptor-mediated antigen recognition. On the basis of our previous data, we postulated that formation of the viral synapse was triggered by a conjunction of two signals, one from HTLV-1 infection of the T-cell and one from cell-cell contact. We have recently identified ICAM-1 engagement as a cell-contact signal that causes the microtubule polarization associated with the virological synapse. Here we used confocal microscopy of T-lymphocytes naturally infected with HTLV-1 or transfected with individual HTLV-1 genes to investigate the role of the viral transcriptional transactivator protein Tax. Polarization of the microtubules was induced by cell-cell contact or by cross-linking T-cell surface molecules with monoclonal antibodies adsorbed to latex beads. We show that Tax, which is mainly found in the nucleus, is also present at two specific extranuclear sites as follows: around the microtubule organizing center in association with the cis-Golgi and in the cell-cell contact region. We show that expression of Tax provides an intracellular signal that synergizes with ICAM-1 engagement to cause the T-cell microtubule polarization observed at the virological synapse.

Actin Cytoskeleton↗
PubMed2005

Engagement of specific T-cell surface molecules regulates cytoskeletal polarization in HTLV-1-infected lymphocytes.

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.

CD4-Positive T-Lymphocytes↗
PubMed2005

International Retrovirology Association brings together scientists and clinicians to bridge discoveries about human T-lymphotropic viruses from the laboratory to clinical trials.

Human T-lymphotropic virus type 1 (HTLV-1) and HTLV-2 were among the first human retroviruses discovered in the early 1980's. The International Retrovirology Association is an organized effort that fostered the efforts of scientists and clinicians to form interdisciplinary groups to study this group of retroviruses and their related diseases. The Association promotes excellent science, patient education, and fosters the training of young scientists to promote "bench-to-bedside" research. The International Conference on Human Retrovirology: HTLV and Related Viruses sponsored by the Association supports clinicians and researchers in the exchange of research findings and stimulation of new research directions. This years conference will be held from June 22 to 25, in Montego Bay, Jamaica http://www.htlvconference.org.jm/. Since its inception in 1988, these conferences have provided a highly interactive forum for the global community of HTLV scientists. This is of particular importance as HTLV research enters its third decade and a new generation of scientists takes over this important work. Many of the scientists attending the meeting will be from developing countries where HTLV is endemic, consistent with the history of international collaborations that have characterized HTLV research. The International Conference on Human Retrovirology provides a unique opportunity for researchers of all disciplines interested in HTLV infections to meet their peers and to address the questions facing clinicians and scientists who study retroviruses, like HTLV.

Biomedical Research↗
PubMed2005

The seroepidemiology of human T-lymphotropic viruses: types I and II in Europe: a prospective study of pregnant women.

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.

Europe↗
PubMed2005

A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load.

The CD8+ lymphocyte response is a main component of host immunity, yet it is difficult to quantify its contribution to the control of persistent viruses. Consequently, it remains controversial as to whether CD8+ cells have a biologically significant impact on viral burden and disease progression in infections such as human immunodeficiency virus-1 and human T-lymphotropic virus type I (HTLV-I). Experiments to ascertain the impact of CD8+ cells on viral burden based on CD8+ cell frequency or specificity alone give inconsistent results. Here, an alternative approach was developed that directly quantifies the impact of CD8+ lymphocytes on HTLV-I proviral burden by measuring the rate at which HTLV-I-infected CD4+ cells were cleared by autologous CD8+ cells ex vivo. It was demonstrated that CD8+ cells reduced the lifespan of infected CD4+ cells to 1 day, considerably shorter than the 30 day lifespan of uninfected cells in vivo. Furthermore, it was shown that HTLV-I-infected individuals vary considerably in the rate at which their CD8+ cells clear infected cells, and that this was a significant predictor of their HTLV-I proviral load. Forty to 50 % of between-individual variation in HTLV-I proviral load was explained by variation in the rate at which CD8+ cells cleared infected cells. This novel approach demonstrates that CD8+ cells are a major determinant of HTLV-I proviral load. This assay is applicable to quantifying the CD8+ cell response to other viruses and malignancies and may be of particular importance in assessing vaccines.

Adult↗
PubMed2004

The role of CTLs in persistent viral infection: cytolytic gene expression in CD8+ lymphocytes distinguishes between individuals with a high or low proviral load of human T cell lymphotropic virus type 1.

The proviral load in human T cell lymphotropic virus type 1 (HTLV-1) infection is typically constant in each infected host, but varies by >1000-fold between hosts and is strongly correlated with the risk of HTLV-1-associated inflammatory disease. However, the factors that determine an individual's HTLV-1 proviral load remain uncertain. Experimental evidence from studies of host genetics, viral genetics, and lymphocyte function and theoretical considerations suggest that a major determinant of the equilibrium proviral load is the CD8+ T cell response to HTLV-1. In this study, we tested the hypothesis that the gene expression profile in circulating CD8+ and CD4+ lymphocytes distinguishes between individuals with a low proviral load of HTLV-1 and those with a high proviral load. We show that circulating CD8+ lymphocytes from individuals with a low HTLV-1 proviral load overexpressed a core group of nine genes with strong functional coherence: eight of the nine genes encode granzymes or other proteins involved in cell-mediated lysis or Ag recognition. We conclude that successful suppression of the HTLV-1 proviral load is associated with strong cytotoxic CD8+ lymphocyte activity in the peripheral blood.

CD4-Positive T-Lymphocytes↗
PubMed2004

Human T cell lymphotropic virus (HTLV) type-1-specific CD8+ T cells: frequency and immunodominance hierarchy.

Human T cell lymphotropic virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We used interferon- gamma enzyme-linked immunospot assays with overlapping peptides spanning the entire HTLV-1 proteome to test whether the HTLV-1-specific CD8(+) T cells differed significantly in frequency or immunodominance hierarchy between patients with HAM/TSP and asymptomatic carriers and whether the frequency correlated with provirus load. Tax was the immunodominant target antigen. There was no significant qualitative or quantitative difference in the HTLV-1-specific CD8(+) T cell response between the 2 groups. Virus-specific CD8(+) T cell frequency alone does not indicate the effectiveness of the cytotoxic T lymphocyte response in controlling provirus load at equilibrium.

CD8-Positive T-Lymphocytes↗
PubMed2004

Human T cell lymphotropic virus type I (HTLV-I)-specific CD4+ T cells: immunodominance hierarchy and preferential infection with HTLV-I.

CD4(+) T cells predominate in early lesions in the CNS in the inflammatory disease human lymphotropic T cell virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but the pathogenesis of the disease remains unclear and the HTLV-I-specific CD4(+) T cell response has been little studied. We quantified the IFN-gamma-producing HTLV-I-specific CD4(+) T cells, in patients with HAM/TSP and in asymptomatic carriers with high proviral load, to test two hypotheses: that HAM/TSP patients and asymptomatic HTLV-I carriers with a similar proviral load differ in the immunodominance hierarchy or the total frequency of specific CD4(+) T cells, and that HTLV-I-specific CD4(+) T cells are preferentially infected with HTLV-I. The strongest CD4(+) T cell response in both HAM/TSP patients and asymptomatic carriers was specific to Env. This contrasts with the immunodominance of Tax in the HTLV-I-specific CD8(+) T cell response. The median frequency of HTLV-I-specific IFN-gamma(+) CD4(+) T cells was 25-fold greater in patients with HAM/TSP (p = 0.0023, Mann-Whitney) than in asymptomatic HTLV-I carriers with a similar proviral load. Furthermore, the frequency of CD4(+) T cells infected with HTLV-I (expressing Tax protein) was significantly greater (p = 0.0152, Mann-Whitney) among HTLV-I-specific cells than CMV-specific cells. These data were confirmed by quantitative PCR for HTLV-I DNA. We conclude that the high frequency of specific CD4(+) T cells was associated with the disease HAM/TSP, and did not simply reflect the higher proviral load that is usually found in HAM/TSP patients. Finally, we conclude that HTLV-I-specific CD4(+) T cells are preferentially infected with HTLV-I.

Amino Acid Sequence↗
PubMed2003

Drug resistance is uncommon in pregnant women with low viral loads taking zidovudine monotherapy to prevent perinatal HIV transmission.

Zidovudine monotherapy is used to reduce perinatal HIV transmission in women with low viral loads. There are few data on the risk of drug resistance in this select cohort of women. We determined the prevalence of newly acquired mutations conferring reduced sensitivity to zidovudine after exposure during pregnancy, and found that the development of mutations was uncommon and was restricted to women treated before 1998 who had higher baseline viral loads than those currently recommended monotherapy.

Anti-HIV Agents↗
PubMed2003

Activation of interleukin-13 expression in T cells from HTLV-1-infected individuals and in chronically infected cell lines.

Human T-cell leukemia virus type 1 (HTLV-1) infection profoundly alters T-cell gene expression, and the dysregulated synthesis of cytokines could influence the course and pathologic consequences of infection. In the process of screening T-cell lines for T helper 1 (Th1) and Th2 cytokine mRNAs, we observed that interleukin-13 (IL-13) mRNA was highly expressed in HTLV-1-infected, IL-2-dependent T-cell lines. IL-9 and interferon gamma (IFN-gamma) mRNAs were also expressed at high levels in chronically infected cell lines. IL-5 mRNA was detected in 60% of the HTLV-1-infected cell lines, but mRNAs for IL-4, IL-10, IL-2, and IL-15 were either below detection limits or did not correlate with HTLV-1 infection. Transcriptional activation of the IL-13 promoter by the HTLV-1 Tax trans-regulatory protein was demonstrated in Jurkat T cells transiently transfected with an IL-13 promoter-reporter plasmid. The clinical relevance of these observations was demonstrated by immunofluorescent staining and flow cytometry of lymphocytes obtained from HTLV-1-infected patients. These studies revealed that IL-13 production was directly related to the level of Tax expression in the infected CD4+ T cells soon after in vitro culture. As IL-13 plays key roles in tumor immunosurveillance, asthma, and central nervous system inflammation, it may contribute to the pathophysiology of HTLV-1-associated diseases.

Case-Control Studies↗