Jack T Stapleton

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (144)902.34 Total impact

  • The Journal of infectious diseases. 11/2014;
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    ABSTRACT: Background: An avian H7N9 influenza outbreak has caused morbidity with high mortality in China since 2013. To compare the safety and immunogenicity of H7N9 vaccine with or without MF59 adjuvant, we conducted a phase 2 clinical trial at four NIAID-funded Vaccine and Treatment Evaluation Units (VTEUs). Methods: Healthy adults aged 19-64 years were given influenza A/Shanghai/2/13 (H7N9) inactivated virus vaccine IM on days 0 and 21 at nominal antigen (Ag) doses of 3.75, 7.5, 15, or 45µg. Field site mixing of Ag with MF59 (9.75 mg squalene/0.25ml) was performed for both, one or neither of the 2 doses. Key study outcomes were antibody (Ab) titers on d42, vaccine-related serious adverse events, and solicited local and systemic symptoms post-vaccination. B and T cells assays were performed on a subset of 37 participants. ClinicalTrials.gov # NCT01938742. Results: 700 subjects were enrolled. Hemagglutination inhibition (HAI) and neutralizing Ab (NAb) were minimal after 2 doses of unadjuvanted vaccine or 1 dose of adjuvanted vaccine (any Ag dose). For 3.75 µg + MF59, d42 HAI seroconversion (SC; 4-fold titer rise to >40) occurred in 60% (95% CI, 50-70); and geometric mean titer (GMT) was 35 (95% CI, 26-47). Higher doses of Ag did not increase response. For NAb, the 3.75 µg + MF59 group had a day 42 SC rate of 84% (95% CI, 76-91) with a GMT of 85 (95% CI, 69-104). Mixing adjuvant with only the first of 2 15 µg doses was comparable to 2 adjuvanted 15 µg doses. Recent seasonal flu vaccination and aging attenuated Ab responses. Ab responses correlated with d8 Ab-secreting B cells (ASC; r=0.43; p=0.01) and CD4+ICOS+CXC3+CXCR5+ T follicular helper cells (TFH; r=0.57; p<0.001) in blood, but not d0 memory B cells. TFH recognized H7 Ag, produced IL21, and trended higher with MF59. There were no vaccine-related serious adverse events and reactogenicity was mostly mild with more frequent local symptoms seen with adjuvanted doses. Conclusion: Point-of-use mixing and administration of 2 doses of H7N9 vaccine (3.75 µg) with MF59 produced d42 SC in 60% of subjects. D8 ASC and CD4 TFH levels correlated with d42 HAI Ab response. The study indicates potential value in this rapid response tactic against H7N9. Remaining questions include Ab duration and protective efficacy.
    IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
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    ABSTRACT: Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.
    JAMA. 10/2014; 312(14):1409-1419.
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    ABSTRACT: Some retrospective studies suggest an association between infection with GB-virus C (GBV-C) and non-Hodgkin lymphoma (NHL). We evaluated this association prospectively in a nested case-control study within the U.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Cases (N=658) and controls (N=1,316) were individually-matched by age, sex, race/ethnicity, timing of study entry and sample selection. Pre-diagnostic PLCO serum samples were tested for GBV-C RNA (as a measure of active infection) and E2 antibody (active or resolved infection). Logistic regression was used to estimate odds ratios (ORs) for the association between GBV-C and NHL overall and NHL subtypes. Twelve cases (1.8%) and 7 controls (0.5%) were GBV-C RNA positive. GBV-C RNA positivity was associated with NHL overall (OR=3.43, 95% CI=1.35-8.71) and, based on small numbers, diffuse large B-cell lymphoma (OR=5.31, 95% CI=1.54-18.36). The association with NHL persisted when the interval between testing and selection was greater than 4 years (OR=6.00, 95% CI= 1.21- 29.73). In contrast, E2 antibody-positivity was not associated with NHL risk (OR=1.08, 95% CI=0.74-1.58). Our study demonstrates that GBV-C infection precedes development of NHL. GBV-C infection may play an etiologic role in a small proportion of NHL cases, perhaps by causing chronic immune stimulation or impaired immunosurveillance.
    Cancer research. 08/2014;
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    ABSTRACT: Human Pegivirus (HPgV; previously called GB virus C/hepatitis G virus) has limited pathogenicity despite causing persistent infection, and is associated with prolonged survival in HIV-infected individuals. Although HPgV RNA is found in and produced by T and B lymphocytes, the primary permissive cell type(s) are unknown. We quantified HPgV RNA in highly purified CD4+ and CD8+ T cells, including naïve, central memory, and effector memory populations, and in B cells (CD19+), NK cells (CD56+) cells and monocytes (CD14+) using real time RT-PCR. Single genome sequencing was performed on virus within individual cell types to estimate genetic diversity among cell populations. HPgV RNA was present in CD4+ and CD8+ T lymphocytes (9 of 9 subjects), B lymphocytes (7 of 10), NK cells and monocytes (both 4 of 5). HPgV RNA levels were higher in naïve (CD45RA+) CD4+ cells than in central memory and effector memory cells (p<0.01). HPgV sequences were highly conserved between patients (0.117 ± 0.02 substitutions per site; range 0.58-0.14) and within subjects (0.006 ± 0.003 substitutions per site; range 0.006-0.010). The non-synonymous/synonymous substitution ratio was 0.07 suggesting low selective pressure. CFSE-labeled HPgV RNA-containing particles precipitated by a commercial exosome isolation reagent delivered CSFE to uninfected monocytes, NK cells, T and B lymphocytes, and HPgV RNA was transferred to peripheral blood mononuclear cells with evidence of subsequent viral replication. Thus, HPgV RNA-containing serum particles including microvesicles may contribute to delivery of HPgV to PBMCs in vivo, explaining the apparent broad tropism of this persistent human RNA virus.
    Journal of General Virology 03/2014; · 3.13 Impact Factor
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    ABSTRACT: The 2005 consensus proposal for the classification of hepatitis C virus (HCV) presented an agreed and uniform nomenclature for HCV variants and the criteria for their assignment into genotypes and subtypes. Since its publication, the available dataset of HCV sequences has vastly expanded through advancement in nucleotide sequencing technologies and an increasing focus on the role of HCV genetic variation in disease and treatment outcomes. The current study represents a major update to the previous consensus HCV classification, incorporating additional sequence information derived from over 1,300 (near-)complete genome sequences of HCV available on public databases in May 2013. Analysis resolved several nomenclature conflicts between genotype designations and using consensus criteria created a classification of HCV into seven confirmed genotypes and 67 subtypes. There are 21 additional complete coding region sequences of unassigned subtype. The study additionally describes the development of a Web resource hosted by the International Committee for Taxonomy of Viruses (ICTV) that maintains and regularly updates tables of reference isolates, accession numbers, and annotated alignments (http://talk.ictvonline.org/links/hcv/hcv-classification.htm). The Flaviviridae Study Group urges those who need to check or propose new genotypes or subtypes of HCV to contact the Study Group in advance of publication to avoid nomenclature conflicts appearing in the literature. While the criteria for assigning genotypes and subtypes remain unchanged from previous consensus proposals, changes are proposed in the assignment of provisional subtypes, subtype numbering beyond “w,” and the nomenclature of intergenotypic recombinant. Conclusion: This study represents an important reference point for the consensus classification of HCV variants that will be of value to researchers working in clinical and basic science fields. (Hepatology 2014;59:318-327)
    Hepatology 01/2014; 59(1). · 12.00 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) and GB virus type C (GBV-C) are associated with impaired T cell function despite the fact that HCV replicates in hepatocytes and GBV-C in a small proportion of lymphocytes. Recently, we showed that HCV and GBV-C E2-envelope proteins reduce T cell activation via the T cell receptor (TCR) by competing for phosphorylation with a critical kinase in the TCR signaling cascade (Lck). E2 interfered with TCR signaling in E2 expressing cells and in bystander cells. The bystander effect was mediated by virus particles and extracellular microvesicular particles (exosomes). Multiple kinase substrate sites are predicted to reside on viral structural proteins and based on bioinformatic predictions, many RNA virus pathogens may interfere with TCR signaling via a similar mechanism. Identification of T cell inhibitory effects of virus structural proteins may provide novel approaches to enhance the immunogenicity and memory of viral vaccines.
    Transactions of the American Clinical and Climatological Association 01/2014; 125:14-26.
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    ABSTRACT: Background Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women. Methods In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26–35 and 36–45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047. Findings The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1–94·0), in the 26–35 years age group (83·5%, 45·0–96·8), and in the 36–45 years age group (77·2%, 2·8–96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6–95·9) and HPV 45 (76·9%, 18·5–95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (<1%) and eight (<1%) of these events, respectively, were believed to be related to vaccination. Interpretation In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45. Funding GlaxoSmithKline Biologicals SA.
    Lancet. 01/2014;
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    ABSTRACT: During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1)/programmed death-1-ligand (PD-L1) interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL) activity. Despite antiretroviral therapy (ART), attenuated anti-HIV CTL functions present a major hurdle towards curative measures requiring viral eradication. Therefore, deeper understanding of the mechanisms underlying impaired CTL is crucial before HIV viral eradication is viable. The generation of robust CTL activity necessitates interactions between antigen-presenting cells (APC), CD4+ and CD8+ T cells. We have shown that in vitro, IL-10hiPD-L1hi regulatory B cells (Bregs) directly attenuate HIV-specific CD8+-mediated CTL activity. Bregs also modulate APC and CD4+ T cell function; herein we characterize the Breg compartment in uninfected (HIVNEG), HIV-infected "elite controllers" (HIVEC), ART-treated (HIVART), and viremic (HIVvir), subjects, and in vitro, assess the impact of Bregs on anti-HIV CTL generation and activity after reactivation of HIV latent reservoirs using suberoylanilide hydroxamic acid (SAHA). We find that Bregs from HIVEC and HIVART subjects exhibit comparable IL-10 expression levels significantly higher than HIVNEG subjects, but significantly lower than HIVVIR subjects. Bregs from HIVEC and HIVART subjects exhibit comparable PD-L1 expression, significantly higher than in HIVVIR and HIVNEG subjects. SAHA-treated Breg-depleted PBMC from HIVEC and HIVART subjects, displayed enhanced CD4+ T-cell proliferation, significant upregulation of antigen-presentation molecules, increased frequency of CD107a+ and HIV-specific CD8+ T cells, associated with efficient elimination of infected CD4+ T cells, and reduction in integrated viral DNA. Finally, IL-10-R and PD-1 antibody blockade partially reversed Breg-mediated inhibition of CD4+ T-cell proliferation. Our data suggest that, possibly, via an IL-10 and PD-L1 synergistic mechanism; Bregs likely inhibit APC function and CD4+ T-cell proliferation, leading to anti-HIV CTL attenuation, hindering viral eradication.
    PLoS ONE 01/2014; 9(4):e92934. · 3.53 Impact Factor
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    ABSTRACT: GB Virus C (GBV-C) is a non-pathogenic flavivirus, commonly found in HIV infected patients. Studies suggest a survival benefit of GBV-C viremia in HIV infection. Impact of GBV-C viremia was evaluated on clinical outcome in multidrug-resistant HIV. The OPTIMA study enrolled advanced multidrug-resistant HIV patients with a CD4 count ≤300 cells/mm(3) . This study included a subset of OPTIMA patients. Primary endpoints included AIDS events or death. GBV-C status was assessed at baseline and last time point on study by real-time PCR. Cox proportional hazards models were used to determine if CD4 count (</>100/mm(3) ), treatment assignment, presence or disappearance of GBV-C viremia, GBV-C viral load level and Hepatitis C virus antibody status were associated with outcome. Of 288 patients (98% male, baseline mean age 48 years, HIV viral load 4.67 log10 /ml, and CD4 127 cells/mm(3) ), 62 (21.5%) had detectable GBV-C viremia. The mortality rate for GBV-C infected subjects was lower, 19/62 (30.7%) versus 87/226 (38.5%), and time to death shorter (HR 0.67, 95% CI 0.41-1.11), but the results were not significantly different. The time to development of AIDS events was not different (HR 0.90, 95% CI 0.52-1.53). Among covariates, only CD4 count (HR 0.28, CI 0.19-0.42) had a significant survival effect. A trend in decreased mortality was seen in GBV-C+ patients with CD4 <100/mm(3) in multivariate analyses. GBV-C co-infection in multidrug-resistant HIV infected patients was associated with a trend in improved survival but not decreased AIDS events. Analysis was limited by cohort size. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 11/2013; · 2.37 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):2538-2538. · 8.65 Impact Factor
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    ABSTRACT: GB virus C (GBV-C), a pan-lymphotropic flavivirus capable of persistent infection, is associated with prolonged survival and reduced T-cell activation in HIV-infected patients. GBV-C was associated with reduced CD56brt/CD16 natural killer cell and monocyte activation, and a trend toward reduced B-cell activation by measuring cell surface activation markers or HIV entry coreceptors. The GBV-C association was independent of HIV viral load. Thus, GBV-C may influence non-T-cell immune activation in individuals with HIV infection.
    AIDS (London, England) 07/2013; 27(11):1829-1832. · 4.91 Impact Factor
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    ABSTRACT: Viruses enter into complex interactions within human hosts, leading to facilitation or suppression of each other's replication. Upon coinfection, GB virus C (GBV-C) suppresses HIV-1 replication in vivo and in vitro, and GBV-C coinfection is associated with prolonged survival in HIV-infected people. GBV-C is a lymphotropic virus capable of persistent infection. GBV-C infection is associated with reduced T cell activation in HIV-infected humans, and immune activation is a critical component of HIV disease pathogenesis. We demonstrate that serum GBV-C particles inhibited activation of primary human T cells. T cell activation inhibition was mediated by the envelope glycoprotein E2, because expression of E2 inhibited TCR-mediated activation of Lck. The region on the E2 protein was characterized and revealed a highly conserved peptide motif sufficient to inhibit TCR-mediated signaling. The E2 region contained a predicted Lck substrate site, and substitution of an alanine or histidine for the tyrosine reversed TCR-signaling inhibition. GBV-C E2 protein and a synthetic peptide representing the inhibitory amino acid sequence were phosphorylated by Lck in vitro. The synthetic peptide also inhibited TCR-mediated activation of primary human CD4(+) and CD8(+) T cells. Extracellular microvesicles from GBV-C E2-expressing cells contained E2 protein and inhibited TCR signaling in bystander T cells not expressing E2. Thus, GBV-C reduced global T cell activation via competition between its envelope protein E2 and Lck following TCR engagement. This novel inhibitory mechanism of T cell activation may provide new approaches for HIV and immunoactivation therapy.
    The Journal of Immunology 05/2013; · 5.52 Impact Factor
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    ABSTRACT: Reconciling two quantitative enzyme-linked immunosorbent assay tests for an antibody to an RNA virus, in a situation without a gold standard and where false negatives may occur, is the motivation for this work. False negatives occur when access of the antibody to the binding site is blocked. On the basis of the mechanism of the assay, a mixture of four bivariate normal distributions is proposed with the mixture probabilities depending on a two-stage latent variable model including the prevalence of the antibody in the population and the probabilities of blocking on each test. There is prior information on the prevalence of the antibody, and also on the probability of false negatives, and so a Bayesian analysis is used. The dependence between the two tests is modeled to be consistent with the biological mechanism. Bayesian decision theory is utilized for classification.The proposed method is applied to the motivating data set to classify the data into two groups: those with and those without the antibody. Simulation studies describe the properties of the estimation and the classification. Sensitivity to the choice of the prior distribution is also addressed by simulation. The same model with two levels of latent variables is applicable in other testing procedures such as quantitative polymerase chain reaction tests, where false negatives occur when there is a mutation in the primer sequence. Copyright © 2013 John Wiley & Sons, Ltd.
    Statistics in Medicine 04/2013; · 2.04 Impact Factor
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    ABSTRACT: HIV infection is associated with elevated expression of IL-10 and PD-L1, contributing to impairment of T cell effector functions. In autoimmunity, tumor immunology, and some viral infections, Bregs modulate T cell function via IL-10 production. In this study, we tested the hypothesis that during HIV infection, Bregs attenuate CD8(+) T cell effector function, contributing to immune dysfunction. We determined that in vitro, TLR2-, TLR9-, and CD40L-costimulated Bregs from HIV(-) individuals exhibited a high frequency of cells expressing IL-10 and PD-L1. Compared with Bregs from HIV(-) individuals, a significantly higher percentage of Bregs from HIV(+) individuals spontaneously expressed IL-10 (P=0.0218). After in vitro stimulation with HIV peptides, Breg-depleted PBMCs from HIV(+) individuals exhibited a heightened frequency of cytotoxic (CD107a(+); P=0.0171) and HIV-specific CD8(+) T cells compared with total PBMCs. Furthermore, Breg depletion led to enhanced proliferation of total CD8(+) and CD107a(+)CD8(+) T cells (P=0.0280, and P=0.0102, respectively). In addition, augmented CD8(+) T cell effector function in vitro was reflected in a 67% increased clearance of infected CD4(+) T cells. The observed Breg suppression of CD8(+) T cell proliferation was IL-10-dependent. In HIV(+) individuals, Breg frequency correlated positively with viral load (r=0.4324; P=0.0095), immune activation (r=0.5978; P=0.0005), and CD8(+) T cell exhaustion (CD8(+)PD-1(+); r=0.5893; P=0.0101). Finally, the frequency of PD-L1-expressing Bregs correlated positively with CD8(+)PD-1(+) T cells (r=0.4791; P=0.0443). Our data indicate that Bregs contribute to HIV-infection associated immune dysfunction by T cell impairment, via IL-10 and possibly PD-L1 expression.
    Journal of leukocyte biology 02/2013; · 4.99 Impact Factor
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    ABSTRACT: GB virus type C (GBV-C) is a lymphotropic virus that can cause persistent infection in humans. GBV-C is not associated with any disease, but is associated with reduced mortality in HIV-infected individuals. Related viruses have been isolated from chimpanzees (GBV-Ccpz) and from new world primates (GBV-A). These viruses are also capable of establishing persistent infection. We determined the nucleotide sequence encoding the envelope glycoprotein (E2) of two GBV-Ccpz isolates obtained from the sera of captive chimpanzees. The deduced GBV-Ccpz E2 protein differed from human GBV-C by 31% at the amino acid level. Similar to human GBV-C E2, expression of GBV-Ccpz E2 in a tet-off human CD4+ Jurkat T cell line significantly inhibited the replication of diverse HIV isolates. This anti-HIV replication effect of GBV-Ccpz E2 protein was reversed by maintaining cells in doxycycline to reduce E2 expression. Previously, we found a 17 amino acid region within human GBV-C E2 that was sufficient to inhibit HIV. Although GBV-Ccpz E2 differed by three amino acid differences in this region, the chimpanzee GBV-C 17mer E2 peptide inhibited HIV replication. Similarly, the GBV-A peptide that aligns with this GBV-C E2 region inhibited HIV replication despite sharing only five amino acids with the human GBV-C E2 sequence. Thus, despite amino acid differences, the peptide region on both the GBV-Ccpz and GBV-A E2 protein inhibit HIV replication similar to human GBV-C. Consequently, GBV-Ccpz or GBV-A infection of nonhuman primates may provide an animal model to study GB virus--HIV interactions.
    Journal of General Virology 01/2013; · 3.13 Impact Factor
  • Robert T Rydze, Nirjal Bhattarai, Jack T Stapleton
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    ABSTRACT: BACKGROUND: GB virus C (GBV-C) coinfection is associated with reduced immune activation and a block in CD4(+) T-cell proliferation following interleukin-2 (IL-2) therapy in HIV-infected individuals. We examined peripheral blood mononuclear cells (PBMCs) from HIV-infected subjects with and without GBV-C viraemia to determine if GBV-C correlated with reactivation of latent HIV, T-cell proliferation or T-cell survival following in vitro activation with phytohaemagglutinin A and IL-2 (PHA/IL-2). METHODS: HIV-infected subjects whose HIV viral load was suppressed on combination antiretroviral therapy (cART) for >6 months were studied. PBMCs were cultured with and without PHA/IL-2 and monitored for HIV reactivation, proliferation and survival. GBV-C viraemia and in vitro replication were detected by real-time RT-PCR. HIV reactivation was determined by measuring HIV p24 antigen in culture supernatants. Proliferation was measured by counting viable cells and survival measured by flow cytometry. RESULTS: Of 49 HIV-infected individuals, 26 had GBV-C viraemia. Significantly less HIV reactivation and PBMC proliferation following in vitro activation with PHA/IL-2 was observed in samples from GBV-C viraemic subjects compared with non-viraemic controls. Following 5 weeks in culture, GBV-C replication was associated with preservation of CD4(+) and CD8(+) T-cells compared with non-viraemic controls. CONCLUSIONS: GBV-C appears to inhibit immune activation and IL-2 signalling pathways, which might contribute to a reduction in reactivation of latent HIV from cellular reservoirs. In addition, GBV-C viraemia was associated with a reduction in activation-induced T-cell death. GBV-C-associated T-cell effects could contribute to the observed protective effect of GBV-C coinfection in HIV-infected individuals.
    Antiviral therapy 09/2012; · 3.07 Impact Factor
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    ABSTRACT: Double-negative T cells (DNTCs; ie, CD3(+)CD4(-)CD8(-) T cells) play a role in limiting chronic immune activation. GB virus C (GBV-C) infection is associated with reduced T-cell activation in human immunodeficiency virus (HIV)-infected individuals. T-cell activation and DNTCs were measured in HIV-infected subjects with a nondetectable HIV load. GBV-C-viremic subjects had significantly reduced CD4(+) and CD8(+) T-cell activation (P = .003 and .034, respectively) and significantly increased DNTCs (P = .038), compared with nonviremic subjects. GBV-C load correlated with DNTC percentage (P = .004). Thus, GBV-C infection is associated with an increase in DNTCs, which may contribute to reduced immune activation during HIV infection.
    The Journal of Infectious Diseases 08/2012; 206(9):1469-72. · 5.85 Impact Factor
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    ABSTRACT: GB virus type C (GBV-C) viremia is associated with reduced CD4+ T cell expansion following IL-2 therapy and with a reduction in T cell activation in HIV-infected individuals. The mechanism(s) by which GBV-C might alter T cell activation or IL-2 signaling have not been studied. In this study, we assess IL-2 release, IL-2R expression, IL-2 signaling, and cell proliferation in tet-off Jurkat cells expressing the GBV-C envelope glycoprotein (E2) following activation through the TCR. TCR activation was induced by incubation in anti-CD3/CD28 Abs. IL-2 release was measured by ELISA, STAT5 phosphorylation was assessed by immunoblot, and IL-2Rα (CD25) expression and cell proliferation were determined by flow cytometry. IL-2 and IL-2Rα steady-state mRNA levels were measured by real-time PCR. GBV-C E2 expression significantly inhibited IL-2 release, CD25 expression, STAT5 phosphorylation, and cellular proliferation in Jurkat cells following activation through the TCR compared with control cell lines. Reducing E2 expression by doxycycline reversed the inhibitory effects observed in the E2-expressing cells. The N-terminal 219 aa of E2 was sufficient to inhibit IL-2 signaling. Addition of purified recombinant GBV-C E2 protein to primary human CD4+ and CD8+ T cells inhibited TCR activation-induced IL-2 release and upregulation of IL-2Rα expression. These data provide evidence that the GBV-C E2 protein may contribute to the block in CD4+ T cell expansion following IL-2 therapy in HIV-infected individuals. Furthermore, the effects of GBV-C on IL-2 and IL-2-signaling pathways may contribute to the reduction in chronic immune activation observed in GBV-C/HIV-coinfected individuals.
    The Journal of Immunology 07/2012; 189(5):2211-6. · 5.52 Impact Factor

Publication Stats

3k Citations
902.34 Total Impact Points


  • 2014
    • The University of Edinburgh
      • Centre for Immunity, Infection and Evolution
      Edinburgh, Scotland, United Kingdom
  • 1992–2014
    • University of Iowa
      • • Department of Internal Medicine
      • • Helen C. Levitt Center for Viral Pathogenesis
      • • Department of Biology
      Iowa City, Iowa, United States
  • 2013
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
    • Rush University Medical Center
      Chicago, Illinois, United States
  • 2012
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States
  • 2009–2012
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
    • Edwards Lifesciences
      Irvine, California, United States
    • Boehringer Ingelheim
      Ingelheim, Rheinland-Pfalz, Germany
  • 2011
    • University of Illinois at Chicago
      • Division of Epidemiology and Biostatistics
      Chicago, IL, United States
  • 2008
    • University of Maryland, Baltimore
      • Department of Medicine
      Baltimore, MD, United States
  • 2006
    • Saint Louis University
      Saint Louis, Michigan, United States
    • Universidade Federal de São Paulo
      San Paulo, São Paulo, Brazil
  • 2004
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
    • Duke University Medical Center
      Durham, North Carolina, United States
  • 1988
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States