A5019804998- Hepatitis B Virus Studies
- Hepatitis C virus research
- Liver Disease Diagnosis and Treatment
- Animal Virus Infections Studies
- Mosquito-borne diseases and control
- Respiratory viral infections research
- interferon and immune responses
- Viral Infections and Immunology Research
- Influenza Virus Research Studies
- Synthesis and Catalytic Reactions
- Phosphodiesterase function and regulation
- Virus-based gene therapy research
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Viral Infections and Vectors
- Bacillus and Francisella bacterial research
- Cytomegalovirus and herpesvirus research
- Cancer-related molecular mechanisms research
- Signaling Pathways in Disease
- Plant Virus Research Studies
- Viral gastroenteritis research and epidemiology
- Pneumocystis jirovecii pneumonia detection and treatment
- HIV Research and Treatment
- RNA and protein synthesis mechanisms
- Hepatitis Viruses Studies and Epidemiology
Providence College
2023
GlaxoSmithKline (United States)
2013-2022
Rockefeller University
2004-2019
Research Triangle Park Foundation
2010-2015
Georgetown University Medical Center
2003
University of Kansas Medical Center
1999-2003
Georgetown University
2003
Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low current treatment options (nucleos(t)ide analogs (NAs) pegylated interferons). Bepirovirsen is antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture animal models, bepirovirsen reductions HBV-derived RNAs, DNA viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial the first evaluation...
NS3 protein of dengue virus type 2 has a serine protease domain within the N-terminal 180 residues. NS2B is required for to form an active involved in processing viral polyprotein precursor. The region carboxy terminal conserved motifs present several RNA-stimulated nucleoside triphosphatase (NTPase)/RNA helicases. To define functional domains and NTPase/RNA helicase activities NS3, full-length amino-terminal deletion mutants were expressed Escherichia coli purified. Deletion 160 residues...
RNA structures play key roles in the replication of viruses. Sequence alignment software, thermodynamic folding programs, and classical comparative phylogenetic analysis were used to build models six elements coding region hepatitis C virus (HCV) RNA-dependent polymerase, NS5B. The importance five these was evaluated by site-directed mutagenesis a subgenomic HCV replicon. Mutations disrupting one predicted stem-loop structures, designated 5BSL3.2, blocked replication, implicating it as an...
Positive strand viral replicases are membrane-bound complexes of and host proteins. The mechanism replication the role proteins not well understood. To understand this mechanism, a replicase assay that utilizes extracts from dengue virus-infected mosquito (C6/36) cells exogenous RNA templates is reported in study. 5′- 3′-terminal regions (TR) template RNAs contain conserved elements including complementary (cyclization) motifs stem-loop structures. synthesis vitro requires both 3′-TR present...
Hepatitis C virus (HCV) is a leading cause of chronic liver disease. The identification and characterization key host cellular factors that play role in the HCV replication cycle are important for understanding disease pathogenesis novel antiviral therapeutic targets. Gene expression profiling JFH-1-infected Huh7 cells by microarray analysis was performed to identify genes transcriptionally regulated infection. involved defense mechanisms (apoptosis, proliferation, antioxidant responses),...
Viral replicases of many positive-strand RNA viruses are membrane-bound complexes cellular and viral proteins that include RNA-dependent polymerase (RdRP). The in vitro RdRP assay system utilizes cytoplasmic extracts from dengue viral-infected cells exogenous templates was developed to understand the mechanism replication vivo. Our results indicated synthesis at 3′-untranslated region (UTR) required presence 5′-terminal (TR) two cyclization (CYC) motifs suggesting a functional interaction...
ABSTRACT The hepatitis C virus (HCV) genomic RNA possesses conserved structural elements that are essential for its replication. 3′ nontranslated region (NTR) contains several of these elements: a variable region, the poly(U/UC) tract, and highly X tail, consisting stem-loop 1 (SL1), SL2, SL3. Studies drug-selected, cell culture-adapted subgenomic replicons have indicated an element within NS5B coding 5BSL3.2, forms functional kissing-loop tertiary structure with part NTR, SL2. Recent...
Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger protein (ZAP) is a central and general regulator activity that targets pathogen mRNA stability translation. ZAP diffusely cytoplasmic, but upon infection targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP's correlates with SG localization, what molecular cues are required induce this localization event. Here, we use...
ABSTRACT By using a purified dengue virus RNA-dependent RNA polymerase and subgenomic 770-nucleotide template, it was shown previously that the ratio of de novo synthesis product to hairpin formed inversely proportional increments assay temperatures (20 40°C). In this study, components preinitiation complex are defined as ATP, high concentration GTP (500 μM), polymerase, template RNA. Even when 3′-terminal sequence mutated from -GGUUCU-3′ -GGUUUU-3′, required for initiation, suggesting plays...
Reporter viruses are useful probes for studying multiple stages of the viral life cycle. Here we describe an expanded toolbox fluorescent and bioluminescent influenza A reporter viruses. The enhanced utility these tools enabled kinetic studies attachment, infection, co-infection. Multi-modal bioluminescence positron emission tomography-computed tomography (PET/CT) imaging infected animals revealed that antiviral treatment reduced load, dissemination, inflammation. These new technologies...
Significance We show here that efficient replication of RV-A and RV-C viruses, common respiratory pathogens with positive-strand RNA genomes, requires STING, a host protein canonical function in innate immune responses to DNA viruses. STING is enriched PI4P-containing membranes organelles essential for step the viral genome. Its factor activity highly species-specific, adaptation RV-16 virus murine promotes cells origin. These findings add substantially current understanding factors restrict...
Hepatitis B virus (HBV) chronically infects an estimated 300 million people, and standard treatments are rarely curative. Infection increases the risk of liver cirrhosis hepatocellular carcinoma, consequently, nearly 1 people die each year from chronic hepatitis B. Tools approaches that bring insights into HBV biology facilitate discovery evaluation antiviral drugs in demand. Here, we describe a method to initiate replication HBV, DNA virus, using synthetic RNA. This approach eliminates...
GSK2336805 is an inhibitor of hepatitis C virus (HCV) with picomolar activity on the standard genotype 1a, 1b, and 2a subgenomic replicons exhibits a modest serum shift. was not active 22 RNA DNA viruses that were profiled. We have identified changes in N-terminal region NS5A cause decrease GSK2336805. These mutations 1b replicon showed shifts compound (<13-fold), while 1a had more dramatic impact potency. retained chimeric containing patient sequences from 1 consensus for genotypes 4 5 part...
GSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC50s) in the low nanomolar range genotype 1 and 2 subgenomic replicon system well infectious HCV cell culture system. We have characterized antiviral activity of GSK5852 using chimeric systems genes from additional genotypes sequences clinical isolates patients infected 1a 1b. The inhibitory remained unchanged these intergenotypic intragenotypic systems....
Viruses depend on host-derived factors for their efficient genome replication. Here, we demonstrate that a cellular peptidyl-prolyl cis-trans isomerase (PPIase), cyclophilin B (CyPB), is critical the replication of hepatitis C virus genome. CyPB interacted with HCV RNA polymerase NS5B to directly stimulate its binding activity. Both interference (RNAi)-mediated reduction endogenous expression and induced loss decreased levels Thus, functions as stimulatory regulator in machinery. This...