Shaobing Li

United States Army Medical Research Institute for Infectious Diseases, Maryland, United States

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Publications (13)57.74 Total impact

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    ABSTRACT: BACKGROUND: Rituximab has been successfully used as an experimental therapy in different autoimmune diseases. Recently, a double-blind placebo-controlled phase-2 study in early onset type 1 diabetes showed that rituximab delayed progression of the disease. However, like with any immunosuppressive therapy, there is a concern of opportunistic viral reactivations with the use of rituximab, including herpes and polyomaviruses. OBJECTIVES: To study the incidence of new infections and reactivations with BK, JC, Epstein-Barr and cytomegalovirus (BKV, JCV, EBV and CMV) in T1D participants in the phase-2 rituximab study. STUDY DESIGN: Subjects received 4 weekly doses of rituximab (N=57) or placebo (N=30) during the first month of study. Blood samples obtained at weeks 0, 12, 26, 56 and 78 were assayed for CMV, EBV, BKV and JCV by real-time DNA PCR and serology. RESULTS: EBV reactivations were diagnosed by PCR in 25% of placebo, but none of rituximab recipients (p<0.01). There were no episodes of CMV viremia in either treatment group. BKV viremias were significantly more common in the rituximab recipients (9%) compared with placebo controls (0, p<0.01). No JCV reactivations were detected in this study, but among 6 rituximab and 2 placebo recipients who seroconverted for JCV during the study, only one rituximab recipient had detectable viremia. All infections were asymptomatic. CONCLUSIONS: Four doses of rituximab administered to individuals with early onset T1D decreased the incidence of asymptomatic EBV reactivations, as predicted by the rituximab-mediated elimination of memory B-cells, but increased the frequency of asymptomatic viremias caused by polyomaviruses.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 02/2013; · 3.12 Impact Factor
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    ABSTRACT: Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disorder (PTLD), which has significant morbidity and mortality in transplant recipients. To devise prophylactic measures, we need predictors of PTLD and a better understanding of the physiopathogenesis of the disease. To identify a molecular pattern of EBV gene products in blood that is specific to PTLD and can be used for the diagnosis of this disease. We evaluated the ratio between latent and replicating EBV nucleic acids in individuals with PTLD by comparison with transplant recipients without PTLD and immunocompetent hosts with EBV DNA-emia. Subjects were prospectively identified between July 2009 and October 2010 at the University of Colorado Hospital. EBV DNA, LMP-2A Latency III and BZLF1 Lytic genes mRNA were quantified using real-time PCR. We found that PTLD subjects (N = 7) had significantly higher EBV DNA-emia compared with non-transplant immunocompetent subjects (N = 69; p<0.0001), and transplant recipients without PTLD (N = 105; p<0.0001). The ratios between LMP-2A and BZLF1 mRNA in transplant recipients were significantly lower than in non-transplant subjects (p = 0.04). However, PTLD and non-PTLD transplant recipients displayed similar ratios. These results suggest that EBV replication makes a larger contribution to the circulating EBV DNA in transplant recipients compared with immunocompetent hosts. Transplant recipients seem to lose control over EBV replication, which may contribute to the development of PTLD.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 09/2011; 52(3):231-5. · 3.12 Impact Factor
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    ABSTRACT: Nucleoside analog reverse transcriptase inhibitors (NRTIs) constitute the most commonly used drugs in antiretroviral therapy. NRTIs differ with respect to their host cell toxicity. We compared the in vitro effect of zidovudine (AZT; 2 μg/ml), lamivudine (3TC; 5 μg/ml), stavudine (d4T; 1 μg/ml), and tenofovir (TFV; 1 μg/ml) on Candida cell-mediated immunity (CMI) of peripheral blood mononuclear cells (PBMCs). The concentrations of the active derivative AZT-triphosphate were 4-fold higher in Candida-stimulated compared with unstimulated PBMCs (p = 0.01), but those of 3TC-triphosphate and TFV-diphosphate did not differ significantly. AZT treatment decreased proliferation of unstimulated and Candida-stimulated PBMCs and IFN-γ ELISPOT responses; 3TC decreased proliferation of unstimulated PBMCs only; d4T and TFV decreased proliferation of Candida-stimulated PBMCs only. AZT, but not the other NRTIs, increased unstimulated PBMC apoptosis measured by caspase 3 activity. All NRTIs increased annexin-V-measured apoptosis of Candida-stimulated PBMCs. The effect of d4T on apoptosis of Candida-stimulated PBMCs strongly correlated with its inhibitory effect on mitochondrial DNA synthesis (r² = 0.94; p = 0.007). The other NRTIs did not significantly decrease the mitochondrial:nuclear DNA ratios in Candida-stimulated or unstimulated cultures, suggesting that other mechanisms mediated their effect on apoptosis and CMI. In conclusion, AZT had the most pronounced inhibitory effect on CMI. Further studies are warranted to determine the clinical significance of this observation.
    AIDS research and human retroviruses 10/2010; 27(1):47-55. · 2.18 Impact Factor
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    ABSTRACT: The optimal type and timing of specimens to study the immune responses to cold-adapted influenza vaccine (CAIV) and shedding of vaccine virus are not well established. Healthy adults were vaccinated with CAIV (n=10) or trivalent influenza vaccine (TIV) (n=5). Shedding of vaccine strain influenza B was detected by culture in 6 of 10 CAIV recipients; influenza A was also detected in one of these subjects. Viral shedding by quantitative RT-PCR was detected in 9 of 10 subjects. We detected a > or = 2-fold increase in influenza-specific IgA in nasal wash in 80-100% of CAIV recipients following vaccination, but specific IgG increased in neither nasal wash nor saliva. Recipients of TIV had significant increases in specific serum IgG antibodies. Recipients of both CAIV and TIV had significant increases in IFNgamma-secreting peripheral blood mononuclear cells (PBMCs). PBMCs from subjects receiving CAIV showed a higher proportion of functional, tissue-tropic T-cells (CD4+CD69+CD18+MIP1alpha+) specific for homotypic and heterosubtypic strains of influenza by flow cytometry.
    Vaccine 09/2009; 27(52):7359-66. · 3.77 Impact Factor
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    ABSTRACT: Diverse mutations in the cytomegalovirus (CMV) DNA polymerase (pol) gene confer resistance to one or more of the antiviral drugs ganciclovir, foscarnet or cidofovir. The levels of resistance conferred by specific mutations are variable, ranging from insignificant resistance to triple-drug resistance. Three pol mutations, I521T, P522A and P522L, detected in patients who received antiviral therapy for CMV infection, were studied by recombinant phenotyping to characterize their associated drug resistance. The individual mutations were transferred by homologous recombination into a reference CMV strain modified with a reporter gene and the drug concentrations required to reduce the reporter signal by 50% (IC50) were determined. The mutations I521T and P522A each conferred 3- to 4-fold increases in IC50 to both ganciclovir and cidofovir, while mutation P522L conferred no significant resistance to either drug. None of these mutations conferred foscarnet resistance. The resistance phenotypes of mutations I521T and P522A are as predicted from the known mutation P522S, but divergent results with P522L indicate that different amino acid substitutions at the same position may not have the same effect on drug resistance. New mutations must be individually validated for proper interpretation of genotypic resistance testing.
    Journal of Clinical Virology 06/2008; 43(1):107-9. · 3.29 Impact Factor
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    ABSTRACT: Recombinant phenotyping of cytomegalovirus (CMV) pol region III mutations from clinical specimens showed that T813S and G841A each conferred foscarnet resistance and approximately threefold increased ganciclovir resistance; adding the UL97 mutation C592G increased ganciclovir resistance to approximately sixfold. Bacterial artificial chromosome CMV clones containing pol mutation L845P were nonviable unless repaired with the wild-type sequence.
    Antimicrobial Agents and Chemotherapy 12/2007; 51(11):4160-2. · 4.57 Impact Factor
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    ABSTRACT: HIV-infected patients fail to fully recover cell-mediated immunity despite HAART. To identify regulatory factors, we studied the phenotype and function of in vitro cytomegalovirus (CMV)-stimulated T cells from HAART recipients. CFSE-measured proliferation showed CD4+ and CD8+ cells dividing in CMV-stimulated cultures. Compared with healthy controls, CMV-stimulated lymphocytes from HAART recipients had lower 3H-thymidine incorporation; lower IFNgamma and TNFalpha production; higher CD4+ CD27- CD28- and CD8+ CD27- CD28- frequencies; lower CD4+ CD25hi; and higher FoxP3 expression in CD8+ CD25hi cells. CMV-specific proliferation correlated with higher IFNgamma, TNFalpha and IL10 levels and higher CD4+ perforin+ and CD8+ perforin+ frequencies. Decreased proliferation correlated with higher CD4+ CD27- CD28- frequencies and TGFbeta1 production, which also correlated with each other. Anti-TGFbeta1 neutralizing antibodies restored CMV-specific proliferation in a dose-dependent fashion. In HIV-infected subjects, decreased proliferation correlated with higher CMV-stimulated CD8+ CD25hi frequencies and their FoxP3 expression. These data indicate that FoxP3- and TGFbeta1-expressing regulatory T cells contribute to decreased immunity in HAART recipients.
    Virology 10/2006; 352(2):408-17. · 3.37 Impact Factor
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    ABSTRACT: Infection with cytomegalovirus (CMV) remains a significant cause of morbidity and mortality among hematopoietic cell transplant (HCT) recipients. We describe two pediatric HCT recipients who developed persistent and severe drug-resistant CMV infections. CMV resistance to foscarnet and ganciclovir was detected after only 6 and 11 weeks of therapy, respectively. Viral pol mutations associated with drug resistance in these patients included T838A (a novel mutation) and D588N, which were shown by marker transfer to confer foscarnet and multidrug resistance, respectively. Each of these mutations significantly reduced in vitro replication of CMV, suggesting that they may decrease viral fitness. This finding was further supported by the disappearance of mutations upon withdrawal of antiviral pressure in one patient. Novel antivirals or combination therapy may be required for the treatment of drug-resistant CMV in HCT recipients and perhaps in other severely immunocompromised patients.
    Journal of Clinical Microbiology 02/2005; 43(1):208-13. · 4.07 Impact Factor
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    ABSTRACT: Cord blood (CB) progenitor cells are increasingly used for transplantation in children because of the lower risk of graft-versus-host disease compared with unrelated bone marrow and comparable rates of disease-free survival. There is concern that CB might carry a higher risk of opportunistic infections. Human herpesviruses (HHV) are common pathogens in transplant recipients. CB donors are routinely tested for the presence of anti-cytomegalovirus (CMV) immunoglobulin M to reduce the risk of collecting CMV-infected CB. To assess the incidence of beta and gamma HHV infection of CB collected under standard procedures, we tested 362 CB samples for the presence of CMV; HHV-6, -7, and -8; and Epstein-Barr virus DNA by polymerase chain reaction. HHV-6 DNA was found in 2 samples, yielding an incidence of 0.55% (95% confidence interval, 0.1%-2%). None of the other viral DNAs was found, resulting in a 95% confidence interval of 0% to 1% for the incidence of CMV, Epstein-Barr virus, HHV-7, and HHV-8. Because the seroprevalence of HHV-8 among the CB donors in this study was only 4%, these findings cannot be extended to HHV-8-endemic areas. Our data show that screening prospective CB donors with anti-CMV immunoglobulin M practically eliminates the risk of CB CMV transmission, but HHV-6 warrants CB testing by polymerase chain reaction.
    Biology of Blood and Marrow Transplantation 02/2005; 11(1):35-8. · 3.94 Impact Factor
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    ABSTRACT: We describe clinical and laboratory characteristics of 16 patients with central nervous system (CNS) infection caused by Epstein-Barr virus (EBV) and another pathogen. Seven of 10 immunocompromised patients had coinfection with viruses (3 with cytomegalovirus, 2 with JC virus, and 2 with varicella zoster virus) and 3 with nonviral pathogens (2 with pneumococcus and 1 with Cryptococcus species). Three of 6 immunocompetent patients had coinfections with viruses (1 each with herpes simplex virus, varicella zoster virus, and West Nile virus), and 3 had coinfections with nonviral pathogens (2 with Ehrlichia chaffeensis and 1 with Mycoplasma pneumoniae). The EBV load was similar in immunocompromised and immunocompetent patients and in patients with viral and nonviral coinfections. EBV lytic-cycle mRNA was detected in the cerebrospinal fluid of 5 of 6 tested samples, indicating EBV replication in the CNS during coinfection.
    The Journal of Infectious Diseases 02/2005; 191(2):234-7. · 5.85 Impact Factor
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    ABSTRACT: The role and frequency of human herpesviruses (HHV)-6 and -7 in central nervous system (CNS) diseases of children are unclear. Cerebrospinal fluid samples from 245 pediatric patients (median age 43 days), submitted for evaluations of possible sepsis or of neurologic symptoms, were tested for HHV-6 and HHV-7 DNA by polymerase chain reaction. HHV-6 DNA was found in 3 of 245 samples, and HHV-7 was found in 0 of 245 samples. The three patients with HHV-6 DNA were <2 months of age. HHV-6 was likely pathogenic in two patients with meningitis who lacked evidence of another microbiologic cause. HHV-6 and HHV-7 are uncommon causes of CNS infection in children. HHV-6 may occasionally cause meningitis in young infants.
    Emerging infectious diseases 09/2004; 10(8):1450-4. · 5.99 Impact Factor
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    ABSTRACT: Acute Epstein-Barr virus (EBV) infection of the central nervous system (CNS) is associated with meningoencephalitis and other neurological syndromes and with CNS lymphomas (CNSLs). Diagnosis is based on serological studies and more recently on detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR). We measured EBV DNA by quantitative PCR and EBV mRNA by RT-PCR in the CSF in patients with EBV-associated neurological disorders. EBV was identified as the cause of CNS infection in 28 patients: 14 with CNSL, 10 with encephalitis, and 4 with postinfectious neurological complications. CSF analysis showed that patients with CNSL had high EBV load (mean +/- standard error of 4.8 +/- 0.2 log(10) DNA copies/ml) and low leukocyte counts (22 +/- 7 cells/microl); encephalitis was characterized by high EBV load (4.2 +/- 0.3 log(10) DNA copies/ml) and high leukocyte counts (143 +/- 62 cells/microl); and patients with postinfectious complications showed low EBV load (3.0 +/- 0.2 log(10) DNA copies/ml) with high leukocyte counts (88 +/- 57 cells/microl). Lytic cycle EBV mRNA, a marker of viral replication, was identified in 10 CSF samples from patients with CNSL and encephalitis. These studies demonstrate the utility of quantitative CSF PCR and establish the presence of lytic cycle EBV mRNA in CSF of patients with EBV-associated neurological disease.
    Annals of Neurology 12/2002; 52(5):543-8. · 11.19 Impact Factor
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    ABSTRACT: Respiratory viruses cause severe infections in lung transplant recipients, which require rapid and accurate diagnosis for appropriate management. To evaluate the added benefit of a multiplex PCR for respiratory viruses (influenza [FLU] A and B, respiratory syncytial virus [RSV] A and B and parainfluenza virus [PIV] 1, 2, and 3) complementing rapid respiratory viral culture (RRV) and FLU-A antigen detection (EIA) in this transplant population. Over 6 months, 116 nasal washes and bronchoalveolar lavages, obtained from 72 lung transplant recipients with symptoms of upper or lower respiratory tract infections, were tested in real time by RRV and FLU-A EIA, and batched frozen by PCR. One or more methods recognized a respiratory virus in 31 (27%) specimens, including 15 FLU-A, nine RSV and seven PIV. PCR identified 26 of 31 positive samples demonstrating a sensitivity of 84%, higher than RRV (67%) or EIA (54%). PCR, RRV and EIA detected 60, 80 and 54%, respectively, FLU-A samples. PCR and RRV were equivalent for RSV-A, PIV-2 and 3, but PCR found a significantly higher number of RSV-B and PIV-1. These data indicate that routine use of PCR will enhance the number and speed with which viral respiratory tract infections are diagnosed in lung transplant recipients.
    Journal of Clinical Virology 09/2002; 25(2):171-5. · 3.29 Impact Factor

Publication Stats

250 Citations
57.74 Total Impact Points

Institutions

  • 2013
    • United States Army Medical Research Institute for Infectious Diseases
      Maryland, United States
  • 2005–2011
    • University of Colorado
      • • Division of General Internal Medicine
      • • Department of Pediatrics
      • • Division of Infectious Diseases
      Denver, CO, United States
  • 2007–2008
    • Oregon Health and Science University
      Portland, Oregon, United States