Jack T Stapleton

Minneapolis Veterans Affairs Hospital, Minneapolis, Minnesota, United States

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Publications (156)1088.89 Total impact

  • PLoS Pathogens 09/2015; 11(9):e1005183. DOI:10.1371/journal.ppat.1005183 · 7.56 Impact Factor
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    ABSTRACT: Human Pegivirus (HPgV, formally GB virus C) infects lymphocytes and NK cells in vivo, and infection is associated with reduced T cell and NK cell activation in HIV-infected individuals. The mechanism by which HPgV inhibits NK cell activation has not been assessed. Following IL-12 stimulation, IFNγ expression was lower in HIV-HPgV co-infected subjects compared to HIV mono-infected subjects (p=0.02). In addition, HPgV positive human sera, extracellular vesicles containing E2 protein, recombinant E2 protein and synthetic E2 peptides containing a predicted Tyk2 interacting motif inhibited NK cell IL-12-mediated IFNγ release. E2 protein also inhibited Tyk2 activation following IL-12 stimulation. In contrast, cytolytic NK cell function was not altered by HPgV. Inhibition of NK cell-induced proinflammatory/antiviral cytokines may contribute to both HPgV persistence and reduced immune activation during HIV-coinfection. Understanding mechanisms by which HPgV alters immune activation may contribute towards novel immunomodulatory therapies to treat HIV and inflammatory diseases. Published by Elsevier Inc.
    Virology 07/2015; 485:116-127. DOI:10.1016/j.virol.2015.07.008 · 3.32 Impact Factor
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    ABSTRACT: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration. 524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×10(7) TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination. Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P=0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P=0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months. After second vaccination, geometric mean neutralization titers were 77.6, 45.2 and 54.4 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders in each group was 100/145 (69.0%), 70/148 (47.3%) and 82/146 (56.2%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group. Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses). Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 07/2015; DOI:10.1016/j.vaccine.2015.06.075 · 3.62 Impact Factor
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    ABSTRACT: This query of North American infectious diseases (ID) physicians reviews current and anticipated practice patterns related to HCV care. Fewer than 20% of survey respondents evaluated and/or treated >10 HCV-infected individuals in the past year. We review HCV practice patterns, barriers to management, and education among ID physicians. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Clinical Infectious Diseases 05/2015; 61(5). DOI:10.1093/cid/civ384 · 8.89 Impact Factor
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    Ernest T Chivero · Jack T Stapleton
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    ABSTRACT: Human Pegivirus (HPgV; originally called GB virus C/hepatitis G virus) is an RNA virus within the Pegivirus genus of the Flaviviridae that commonly causes persistent infection. Worldwide, approximately 750 million people are actively infected (viremic) and an estimated 0.75 to 1.5 billion people have evidence of prior HPgV infection. No causal association between HPgV and disease has been identified; however, several studies describe a beneficial relationship between persistent HPgV infection and survival in HIV-infected individuals. The beneficial effect appears to be related to a reduction in host immune activation. HPgV replicates well in vivo (> 1x107 genome copies detected per ml plasma); however, the virus grows poorly in vitro and systems to study this virus are limited. Consequently, mechanisms of viral persistence and host immune modulation remain poorly characterized, and the primary permissive cell type(s) has not yet been identified. HPgV RNA is found in liver, spleen, bone marrow, and peripheral blood mononuclear cells (PBMCs), including T and B lymphocytes, NK cells, and monocytes, although the mechanism of cell-to-cell transmission is unclear. HPgV RNA is also present in serum microvesicles with properties of exosomes. These microvesicles are able to transmit viral RNA to PBMCs in vitro, resulting in productive infection. This review summarizes existing data on HPgV cellular tropism, the effect of HPgV on immune activation in various PBMCs and discusses how this may influence viral persistence. We conclude that an increased understanding of HPgV replication and immune modulation may provide insights into persistent RNA viral infection of humans.
    Journal of General Virology 02/2015; 96(7). DOI:10.1099/vir.0.000086 · 3.18 Impact Factor
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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.
    The Lancet 12/2014; 384(9961). DOI:10.1016/S0140-6736(14)60920-X · 45.22 Impact Factor
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    ABSTRACT: Background: An association between GB virus C (GBV-C) and improved outcomes of human immunodeficiency virus (HIV) infection has been reported in HIV-positive individuals with active GBV-C coinfection. This study provides insights into the immune mechanisms underlying the protective role of GBV-C in HIV-infected patients. Methods: The concentrations of 64 cytokines and chemokines were measured in plasma samples obtained from the Viral Activation Transfusion Study cohort before transfusion and longitudinally from 30 patients positive for both HIV and GBV-C (hereafter, "cases") and 30 patients positive for HIV and negative for GBV-C (hereafter, "controls"). Results: Cases had lower HIV viral loads and higher CD4 T-cell counts than controls after acquisition of GBV-C infection. Most of the modulated cytokines and chemokines were reduced after GBV-C detection, including many proinflammatory cytokines, suggesting an overall antiinflammatory effect of GBV-C in HIV-positive subjects. Most pathways and functions of the measured cytokines were downregulated in cases, except cell death pathways, which were upregulated in various cell subsets in the 3 months after GBV-C detection. Conclusions: GBV-C has a protective effect, in part through a competition mechanism leading to decreased inflammation and improved HIV disease outcome in cases. Further studies are necessary to establish whether GBV-C may have deleterious effects on the host at the cellular level, including depleting the cells that are the targets of HIV.
    The Journal of Infectious Diseases 11/2014; 211(10). DOI:10.1093/infdis/jiu660 · 6.00 Impact Factor
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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
  • Cody Chastain · Susan E. Beekmann · Todd Hulgan · Jack Stapleton
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    ABSTRACT: Background: Hepatitis C (HCV) is a prevalent cause of morbidity and mortality. Updated screening guidelines, public awareness campaigns, and new direct-acting antiviral agents are likely to increase the number of patients seeking HCV care. Infectious diseases (ID) physicians have been identified as a group well suited to manage HCV, but the current and anticipated role of ID physicians has not been sufficiently evaluated. Methods: Adult ID physicians were surveyed regarding their opinions and current practices related to HCV care through the Emerging Infections Network (EIN) via a 10-question survey. Results: Of 1,172 EIN members in the U.S., Canada, and Puerto Rico, 550 (47%) responded. Most (71%) responded that ID physicians should evaluate and/or treat all HCV infections with gastroenterology/hepatology support, while a minority (25%) responded that ID physicians should only evaluate and/or treat patients with mild-moderate liver fibrosis or HIV co-infection. Overall, 54% of respondents currently evaluate and/or treat HCV infection in some capacity, either as HCV mono-infection (40%) and/or HIV/HCV co-infection (47%). Fifty-two percent of physicians who do not currently evaluate and/or treat HCV mono-infection indicated interest in doing so in the future. Factors influencing this decision include clinical capacity/infrastructure, interferon-free regimens for all genotypes, and training/experience. Respondents who do not plan to evaluate and/or treat HCV mono-infection in the future (27%) most commonly cited insufficient capacity/infrastructure, lack of desire, and inadequate training/experience as their rationale. Most ID physicians (61%) did not feel that graduate medical education prepared them to evaluate and/or treat HCV, and members indicated a need for a broad range of training resources. Conclusion: More than 90% of respondents believe that ID physicians should be active in HCV management. The majority of ID physicians who wish to manage HCV mono-infection already provide this service, although many may increase this area of their practice. Expanding graduate medical education, emphasizing continuing medical education, and developing novel management paradigms will be necessary to optimize HCV care in the future.
    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 The Journal of the American Medical Association 10/2014; 312(14):1409-1419. DOI:10.1001/jama.2014.12854 · 35.29 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 08/2014; 125:14-26.
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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; 74(19). DOI:10.1158/0008-5472.CAN-14-0209 · 9.33 Impact Factor
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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 04/2014; 9(4):e92934. DOI:10.1371/journal.pone.0092934 · 3.23 Impact Factor
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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; 95(Pt_6). DOI:10.1099/vir.0.063016-0 · 3.18 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 03/2014; 86(3). DOI:10.1002/jmv.23845 · 2.35 Impact Factor
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    ABSTRACT: Unlabelled: 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 01/2014; 59(1). DOI:10.1002/hep.26744 · 11.06 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):2538-2538. DOI:10.1158/1538-7445.AM2013-2538 · 9.33 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. DOI:10.1097/QAD.0b013e328363089f · 5.55 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; 190(12). DOI:10.4049/jimmunol.1300589 · 4.92 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; 32(23). DOI:10.1002/sim.5816 · 1.83 Impact Factor

Publication Stats

4k Citations
1,088.89 Total Impact Points


  • 2014
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
  • 1992–2014
    • University of Iowa
      • • Department of Internal Medicine
      • • Division of Infectious Diseases
      • • Helen C. Levitt Center for Viral Pathogenesis
      • • College of Pharmacy
      Iowa City, Iowa, United States
  • 2012
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States
  • 2009
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2006
    • 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
  • 1998
    • California Pacific Medical Center Research Institute
      • Department of Transplantation
      San Francisco, California, United States
  • 1991
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States
  • 1988
    • University of North Carolina at Chapel Hill
      North Carolina, United States