William Osburn

• PhD
• Professor (Assistant) at Johns Hopkins University

Introduction: Genome-wide association studies (GWAS) have identified multiple novel loci that contribute to CAD pathogenesis, but the mechanisms of these associations remain largely unknown. Research Question: This study aims to functionally characterize the association between the chromosomal GWAS locus for 4q12 and CAD. Methods: We combined compu...

Coagulation Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with cir...

Introduction: Despite the emergence of new lipid-lowering therapies, coronary artery disease (CAD) remains the leading cause of death worldwide. Genome-wide association studies (GWAS) for CAD have discovered multiple novel loci that contribute to CAD pathogenesis. However, limitations in the interpretability of those GWAS associations have hindered...

Introduction: Abnormal levels of the coagulation factor VIII (FVIII) are a risk factor for venous thromboembolism (VTE). Genome-wide association studies have identified novel candidate gene associations that may regulate FVIII levels in humans, including CD36. Hypothesis: We hypothesized that CD36 regulates FVIII release from endothelial cells. Met...

Background Oral contraceptive (OC) use increases venous thromboembolism risk 2-5-fold. Procoagulant changes can be detected in plasma from OC users even without thrombosis, but cellular mechanisms that provoke thrombosis have not been identified. Endothelial cell (EC) dysfunction is thought to initiate venous thromboembolism. It is unknown whether...

Introduction: Human liver endothelial cells (HLEC) are a heterogeneous cell population. Single cell transcriptomics and immunostaining assays have categorized HLEC into two major groups according to their location within the liver lobules (zone 1 or periportal HLEC and zones 2/3 or central venous (CV) HLEC). Hypothesis: Cellular deconvolution of th...

Severe coronavirus disease-19 (COVID-19) is characterized by vascular inflammation and thrombosis. We and others have proposed that the inflammatory response to coronavirus infection activates endothelial cells, leading to endothelial release of pro-thrombotic proteins. These mediators can trigger obstruction of the pulmonary microvasculature, lead...

COVID-19 is characterized by vascular inflammation and thrombosis, including elevations in P-selectin, a mediator of inflammation released by endothelial cells. We tested the effect of P-selectin inhibition on biomarkers of thrombosis and inflammation in patients with COVID-19. Hospitalized patients with moderate COVID-19 were randomly assigned to...

Background A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. Methods In this phase 1–2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vacc...

There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t) ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap i...

Background The development of a safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of elimination efforts, providing the rationale for the first HCV vaccine efficacy trial. Methods In a randomized, multicenter, double-blind, placebo-controlled efficacy trial (NCT01436357), we evaluated a recombi...

A vaccine for hepatitis C virus (HCV) is urgently needed. Development of broadly-neutralizing plasma antibodies during acute infection is associated with HCV clearance, but the viral epitopes of these plasma antibodies are unknown. Identification of these epitopes could define the specificity and function of neutralizing antibodies (NAbs) that shou...

Hepatitis-C Virus (HCV) sequences are often used to establish networks of people who inject drugs (PWID). However, the degree to which within-host evolutionary dynamics affect those inferences has not been carefully studied. Here, we analyzed 702 longitudinally-sampled HCV E1 sequences from 88 HCV+ people who inject drugs (PWID) in the Baltimore Be...

Interactions between the host immune system and the viral variants determine persistence of hepatitis C virus (HCV) infection after the acute phase of infection. This study describes the genetic variability of within‐host HCV viral variants in acute infection and correlates it with host and virus‐related traits and infection outcome. Next generatio...

Human genetic studies demonstrate a link between the 32‐bp deletion that produces a nonfunctional CCR5 receptor (CCR5∆32) and enhanced recovery from acute hepatitis B virus (HBV) infection. To investigate the role of CCR5 in immune responses to acute HBV, we intravenously infected Ccr5+/+ (WT) and Ccr5‐/‐ (KO) mice with a replication‐incompetent ad...

Clinical laboratory-based nucleic acid amplification tests (NAT) play an important role in diagnosing viral infections. However, laboratory infrastructure requirements and their failure to diagnose at the point-of-need (PON) limit their clinical utility in both resource-rich and -limited clinical settings. The development of fast and sensitive PON...

We investigated longitudinal viral clustering among and within subjects in a highly networked cohort of people who inject drugs (PWID). All subjects had estimated dates of infection and two or more E1 sequences (bp 943-1288 relative to H77) with 1 to 14years of follow up. Two methods (HIV-TRACE and PhyloPart) were used to determine clusters. Geneti...

Human genetic studies demonstrate that a non-functional CCR5 receptor sequence variant is associated with enhanced control of acute hepatitis B virus (HBV) infection. To better understand the role of CCR5 in immune responses to HBV, we employed a mouse model of acute HBV in which Ccr5 +/+(WT) or Ccr5 −/−(KO) C57BL/6 mice were intravenously infected...

Broadly-neutralizing monoclonal antibodies (bNAbs) may guide vaccine development for highly variable viruses including hepatitis C virus (HCV), since they target conserved viral epitopes that could serve as vaccine antigens. However, HCV resistance to bNAbs could reduce the efficacy of a vaccine. HC33.4 and AR4A are two of the most potent anti-HCV...

Significant positive correlation between neutralization profiles of HC33.4 and AR4A is observed using subtype 1a-only or subtype 1b-only HCVpp. Each point indicates mean fraction unaffected (Fu) of a single HCvpp by 10 ?g/mL of HC33.4 on the x-axis and AR4A on the y-axis, measured in duplicate. Subtype of HCVpp in each panel is indicated. Fu is inf...

Quantitation of relative sE2 protein concentrations in cell culture supernatants containing 1a154, 1a154_L403F, or 1a154_L438V sE2. Serial dilutions of each sE2 protein were added to ELISA wells that had been pre-coated with GNA-lectin. Bound sE2 was quantitated using an antibody specific for the C-terminal sE2 Histidine tag and an HRP-conjugated s...

Values for infectivity (in relative light units, RLU) of each HCVpp in the panel in the presence of nonspecific human IgG, HC33.4, or AR4A, measured in duplicate. Fu values calculated from these RLU values are also shown, as are the sequence of each E1E2 variant. Each variant in the panel is assigned an arbitrary number to indicate variants that we...

SNAPR analysis of all genotype 1 isolates. SNAPR-values across E1E2 determined using all genotype 1 HCVpp neutraglized by HC33.4 or AR4A. Previously defined HC33.4 and AR4A binding epitopes are indicated (blue and pink), as is hypervariable region 1 (HVR1) (gray), and the portion of E2 crystallized by Kong, et al. ?C? indicates the core protein and...

Introduction of L438V reduces E1E2 fitness, but L403F does not. (A) The indicated mutations were introduced into 1a154 (H77) E1E2, and HCVpp with a luciferase reporter gene were produced. These HCVpp were used to infect Hep3B hepatoma cells, and entry quantitated after 72 hours by measurement of relative light units (RLU). Each data point indicates...

Analysis of experimental variation between Fu measurements. (A) Variation between technical replicate measurements of Fu in the presence of nonspecific human IgG for 113 HCVpp in the neutralization screen. Each point represents the mean of duplicate Fu measurements for one HCVpp on the x-axis and the standard deviation between those values on the y...

Second independent experiment confirming relative binding of 1a154, 1a154_L403F, and 1a154_L438V sE2 to SR-B1-CHO and CD81-CHO cells. Binding of serial dilutions of 1a154, 1a154_L403F, or 1a154_L438V sE2 to CHO-SR-B1 cells or CHO-CD81 cells. Each point was calculated from 10e4 events. Background binding to wild type CHO cells was subtracted from me...

Broadly neutralizing antibodies have been associated with spontaneous clearance of the hepatitis C infection as well as viral persistence by immune escape. Further study of neutralizing antibody epitopes is needed to unravel pathways of resistance to virus neutralization, and to identify conserved regions for vaccine design. All reported broadly ne...

Cross-continental phylogenetic analysis is important to understand subtle molecular differences of currently circulating hepatitis C virus (HCV) subtypes. Existence of such differences can be crucial in pursuing a universal hepatitis C vaccine. We characterized molecular epidemiology of early HCV infections identified across nine cohorts [North Ame...

Background Bayesian evolutionary analysis (coalescent analysis) based on genetic sequences has been used to describe the origins and spread of rapidly mutating RNA viruses such as Influenza, Ebola, HIV and hepatitis C virus (HCV). Methods Full length subtype 1a and 3a sequences from early HCV infections from the International Collaborative of Inci...

Importance: Worldwide, more than 170 million people are infected with hepatitis C virus (HCV), the leading cause of hepatocellular carcinoma and liver transplantation in the United States. Despite recent significant advances in HCV treatment, a vaccine is needed. Control of the HCV pandemic with drug treatment alone is likely to fail due to limite...

Background: Sensitive methods are needed to estimate the population-level incidence of hepatitis C virus (HCV) infection. Methods: We developed an HCV IgG antibody avidity assay by modifying the Ortho 3.0 HCV ELISA, and tested 997 serum or plasma samples from 568 people who inject drugs enrolled in prospective cohort studies. Avidity-based testi...

Background: We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance. Methods: Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV i...

Background: Human immunodeficiency virus (HIV) infection leads to lower rates of hepatitis C virus (HCV) clearance after acute infection, higher HCV viremia, and accelerated progression of HCV-related fibrosis. The mechanisms underlying this acceleration of HCV progression by HIV are poorly understood, but HIV-induced dysfunction in the anti-HCV h...

Hepatitis C virus (HCV) infects the liver and hepatocytes are the major cell type supporting viral replication. Hepatocytes and cholangiocytes derive from a common hepatic progenitor cell that proliferates during inflammatory conditions, raising the possibility that cholangiocytes may support HCV replication and contribute to the hepatic reservoir....

For hepatitis C virus (HCV) and other highly variable viruses, broadly neutralizing mAbs are an important guide for vaccine development. The development of resistance to anti-HCV mAbs is poorly understood, in part due to a lack of neutralization testing against diverse, representative panels of HCV variants. Here, we developed a neutralization pane...

Hepatitis C virus (HCV) infection is still a serious global health burden. Despite improved therapeutic options, a preventative vaccine would be desirable especially in undeveloped countries. Traditionally, highly conserved epitopes are targets for antibody-based prophylactic vaccines. In HCV-infected patients, however, neutralizing antibodies are...

Unlabelled: The contribution of humoral immune responses to spontaneous control of hepatitis C virus (HCV) infection remains unclear. We assessed neutralizing antibody (nAb) responses during acute HCV infection to determine whether infection outcome is associated with the nAb response, specifically, its timing or breadth (neutralization of multipl...

Chemokines and cytokines play a vital role in directing and regulating immune responses to viral infections. Persistent hepatitis C virus (HCV) infection is characterized by the loss of anti-HCV cellular immune responses, while control of HCV infection is associated with maintenance of anti-HCV cellular immune responses. To determine whether plasma...

Background: Detection of hepatitis C virus (HCV) reinfection and intercalation (ie, intermittent recurrent bouts of viremia with homologous virus interspersed with aviremic periods) requires extensive and frequent evaluation and viral sequencing. Methods: HCV infection outcomes were studied prospectively in active injection drug users with recur...

Vaccines designed to prevent or to treat hepatitis C viral infection must achieve maximum cross-reactivity against widely divergent circulating strains. Computer-generated sequences minimize genetic distance between circulating strains, and can be generated as a consensus sequence (most common amino acid at each position) or a representative sequen...

Hepatitis C virus (HCV) was discovered more than two decades ago, but progress towards a vaccine has been slow. HCV infection will spontaneously clear in about 25% of people. Studies of spontaneous HCV clearance in chimpanzees and human beings have identified host and viral factors that could be important in the control of HCV infection and the des...

Hepatitis C virus (HCV) research is hampered by the use of arbitrary representative isolates in cell culture and immunology. The most replicative isolate in vitro is a subtype 2a virus (JFH-1); however, genotype 1 is more prevalent worldwide and represents about 70% of infections in the United States, and genotypes differ from one another by 31% to...

Vaccines designed to prevent or to treat hepatitis C viral infection must achieve maximum cross-reactivity against widely divergent circulating strains. Rational approaches for sequence selection to maximize immunogenicity and minimize genetic distance across circulating strains may enhance vaccine induction of optimal cytotoxic T cell responses. W...

Studies have explored whether spontaneous clearance of hepatitis C virus (HCV) infection decreases the likelihood of reinfection or increases the probability of clearance. This analysis investigates whether the conflicting findings from these studies could be due to differences in frequency of HCV RNA testing. A model simulated the dynamics of HCV...

Hepatitis C virus (HCV) readily establishes chronic infection with exhaustion of HCV-specific T cells and escape from neutralizing antibodies. Spontaneous recovery from chronic infection is rare and has never to our knowledge been studied immunologically. We prospectively studied, from prior to infection through >2 years of follow-up, cytokines, HC...

Proinflammatory cytokines play a critical role in antiviral immune responses. Large-scale genome studies have found correlations between single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 18 promoter and spontaneous control of hepatitis C virus (HCV), suggesting a role in clearance. Plasma IL-18, IL-1β, IL-6, IL-8, IL-12, interferon-γ,...

Methods: Expression of iron metabolism genes was examined by quantitative real-time reverse transcription PCR using liver biopsy samples from patients and 17 normal controls. Serum hepcidin (Hep-20, Hep-22, and Hep-25) levels were measured with chromatography. Results: Expression of transferrin, iron regulatory proteins-1 and -2, divalent metal tra...

We followed patients with ongoing hepatitis C virus (HCV) exposure following control of an initial HCV infection to determine whether primary control conferred protection against future persistent infections. Twenty-two active injection drug users (IDU) who had cleared a primary hepatitis C viremia for at least 60 days were monitored monthly. Reinf...

Loss of NF-E2-related factor 2 (Nrf2) signaling increases susceptibility to acute toxicity, inflammation and carcinogenesis in mice due to the inability to mount adaptive responses. In contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice, although inactivating mutations in Keap1 have been i...

Oxidative stress-mediated destruction of normal parenchymal cells during hepatic inflammatory responses contributes to the pathogenesis of immune-mediated hepatitis and is implicated in the progression of acute inflammatory liver injury to chronic inflammatory liver disease. The transcription factor NF-E2-related factor 2 (Nrf2) regulates the expre...

Human exposures to environmental toxicants have been associated with development of a number of diseases. Animal experiments have identified a number of cytoprotective enzymes under the transcriptional control of NF-E2-related factor 2 (Nrf2) including electrophile conjugation and antioxidative enzymes and enzymes responsible for the production of...

Chronic inflammation has been associated with increased risk of developing cancer. The transcription factor NF-E2-related factor 2 (Nrf2) controls the expression of numerous antioxidative enzymes that have been shown to attenuate acute inflammation. The present study investigated the role of Nrf2 genotype in modulating inflammation-promoted colorec...

Disruption of NF-E2-related factor (Nrf2), a redox-sensitive basic leucine zipper transcription factor, causes early-onset and more severe emphysema due to chronic cigarette smoke. Nrf2 determines the susceptibility of lungs to cigarette smoke-induced emphysema in mice through the transcriptional induction of numerous antioxidant genes. The lungs o...

Mouse embryonic fibroblasts derived from Nrf2-/- mice (N0) and Nrf2+/+ mice (WT) have been used to characterize both basal and diquat (DQ)-induced oxidative stress levels and to examine Nrf2 activation during exposure to DQ-generated superoxide anion. Microarray analysis revealed that N0 cells have similar constitutive mRNA expression of genes resp...

Gene therapy is a promising strategy to modify ischemia-reperfusion injury and rejection after transplantation. We evaluated variables that may affect ex vivo gene transfer to rat lung isografts. Left lungs were harvested and perfused via the pulmonary vein with chloramphenicol acetyltransferase complementary deoxyribonucleic acid complexed with ca...

Our objective were to determine the feasibility, efficacy, and safety of in vivo and ex vivo liposome-mediated gene transfer to lung isografts. Fischer rats were divided into three main groups: (1) Nontransplant setting: Liposome-chloramphenicol acetyl transferase cDNA was intravenously injected, and lungs were harvested at different time points: 2...

Nonviral gene therapy approaches use a plasmid vector to express the desired transgene. We have systematically examined several regulatory elements within plasmid vectors that govern gene expression, e.g., the promoter, enhancer, intron, and polyadenylation signal, by constructing a series of plasmids that differed only in the particular sequence e...