A5044001619- HIV Research and Treatment
- interferon and immune responses
- HIV/AIDS drug development and treatment
- COVID-19 Clinical Research Studies
- SARS-CoV-2 and COVID-19 Research
- RNA regulation and disease
- Respiratory viral infections research
- RNA Research and Splicing
- Herpesvirus Infections and Treatments
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- Microbial infections and disease research
- Plant and Fungal Interactions Research
- Bacteriophages and microbial interactions
- Cytomegalovirus and herpesvirus research
- Conflict Management and Negotiation
- Cytokine Signaling Pathways and Interactions
- Asian Studies and History
- SARS-CoV-2 detection and testing
- Educational Research and Methods
- Cultural and Religious Practices in Indonesia
- Human Resource Development and Performance Evaluation
- Viral-associated cancers and disorders
- Neonatal Respiratory Health Research
- Management and Organizational Studies
University of Colorado Anschutz Medical Campus
2020-2025
University of Colorado Denver
2015-2023
University of Pittsburgh
2021
University of Michigan–Ann Arbor
2021
Mayo Clinic
2009-2014
The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that inhibits by stabilizing and thereby preventing functional disassembly the shell in infected cells. X-ray crystallography, cryo-electron microscopy, hydrogen-deuterium exchange experiments revealed tightly binds two adjoining subunits promotes distal intra- inter-hexamer interactions stabilize curved lattice. In addition, interferes with binding to cellular...
The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis, and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity or neutralizing antibody evasion may drive these novel variants, studies documenting a critical role interferon responses in early control infection, combined presence viral genes limit responses, suggest interferons also influence evolution. Here, we compared potency 17...
Abstract The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity or neutralizing antibody evasion may drive these novel variants, studies documenting a critical role interferon responses in early control infection, combined presence viral genes limit responses, suggest interferons also influence evolution. Here, we compared...
HIV-1 utilizes the cellular protein LEDGF/p75 as a chromosome docking and integration cofactor. The gene, PSIP1, is potential therapeutic target because, like CCR5, depletion of tolerated well by human CD4+ T cells, knockout mice have normal immune systems. RNA interference (RNAi) has been useful for studying LEDGF/p75, but potent cofactor activity small residua can be confounding. Here, in cells with utility HIV research (293T Jurkat), we used transcription activator-like effector nucleases...
Sensing of viral double-stranded RNA by MDA5 triggers abundant but transient interferon-stimulated gene (ISGs) expression. If dsRNA synthesis is made persistent transgenically expressing a picornaviral RNA-dependent polymerase (RdRp) in mice, lifelong activation and marked, global ISG upregulation result. This confers robust protection from diseases contrast to numerous other chronic hyperactivation states, the mice suffer no autoimmune consequences. Here we find they further confound...
LEDGF/p75 can tether over-expressed lentiviral integrase proteins to chromatin but how this underlies its integration cofactor role for these retroviruses is unclear. While a single binding domain (IBD) binds integrase, complex N-terminal ensemble (NDE) interacts with unknown ligands. Whether requires tethering per se, specific NDE-chromatin ligand interactions or other emergent properties of has been elusive. Here we replaced the NDE strongly divergent chromatin-binding modules. The...
The large nucleoporin Nup358/RanBP2 forms eight filaments that project from the nuclear pore into cytoplasm where they function as docking platforms for nucleocytoplasmic transport receptors. RNAi screens have implicated Nup358 in HIV-1 life cycle. 164 C-terminal amino acids of this 3,224 acid protein are a cyclophilin homology domain (Nup358Cyp), which has potential to bind capsid and regulate viral progress integration. Here we examined virological role conditional knockout mouse cells...
Much remains unknown about how TREX1 influences HIV-1 replication: whether it targets full-length viral DNA versus partial intermediates, intracellular protein levels correlate with ISG induction, and digestion of cytoplasmic subsequent cGAS pathway activation affects both initial cycles infection. To answer these questions, we experimentally varied the level showed that this strongly determines innate immunogenicity HIV-1. In addition, several lines evidence, including time-of-addition...
Abstract Background Novel coronavirus disease 2019 (COVID-19) is frequently compared with influenza. The Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) conducts studies on the etiology and characteristics of U.S. hospitalized adults It began enrolling patients COVID-19 hospitalizations in March 2020. Patients influenza were those first months epidemic. Methods Adults aged ≥ 18 years admitted to hospitals 4 sites acute respiratory illness tested by real-time reverse...
Target cell overexpression of the integrase binding domain (IBD) LEDGF/p75 (LEDGF) inhibits HIV-1 replication. The mechanism and protein structure requirements for this dominant interference are unclear. More generally, how when uncoating occurs postentry is poorly defined, it unknown whether within evolving viral core becomes accessible to cellular proteins prior nuclear entry. We used LEDGF address latter question while characterizing determinants IBD antiviral activity. Fusions green...
ABSTRACT BST2/tetherin inhibits the release of enveloped viruses from cells. Primate lentiviruses have evolved specific antagonists (Vpu, Nef, and Env). Here we characterized tetherin proteins species representing both branches order Carnivora. Comparison tiger cat (Feliformia) to dog ferret (Caniformia) genes demonstrated that share a start codon mutation truncated most cytoplasmic tail early in Feliformia lineage (19 27 amino acids, including dual tyrosine motif). Alpha interferon (IFN-α)...
For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not antigen-specific recognition a priori knowledge of the causative agent. However, it is unclear whether effective stable activation can be achieved without triggering harmful autoimmunity other chronic inflammatory sequelae. Here, we show transgenic...
RNA viruses are a major source of emerging and re-emerging infectious diseases around the world. We developed method to identify that is based on fact produce double-stranded (dsRNA) while replicating. Purifying sequencing dsRNA from total isolated infected tissue allowed us recover virus sequences replicated single-stranded (ssRNA) viruses. refer this approach as dsRNA-Seq. By assembling into contigs we identified full length or partial viral genomes varying genome types infecting mammalian...
The study of species- and virus-specific differences in restriction factors their antagonists has been central to deciphering the nature these key host defenses. FIV is an AIDS-causing lentivirus that achieved pandemic spread domestic cat.
Bats are primary reservoirs for multiple lethal human viruses, such as Ebola, Nipah, Hendra, rabies, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East syndrome-related (MERS-CoV), and, most recently, SARS-CoV-2. The innate immune systems of these immensely abundant, anciently diverged mammals remain insufficiently characterized. While bat genomes contain many endogenous retroviral elements indicative past exogenous infections, little is known about restrictions to extant...
Antiviral strategies that target host systems needed for SARS-CoV-2 replication and pathogenesis may have therapeutic potential help mitigate resistance development. Here, we evaluate nafamostat mesylate, a potent broad-spectrum serine protease inhibitor blocks activation of the viral spike protein. is used to infect human polarized mucociliated primary bronchiolar epithelia reconstituted with cells derived from healthy donors, smokers subjects chronic obstructive pulmonary disease....
Immune control of retroviruses is notoriously difficult, a fundamental problem that has been most clinically consequential with the HIV-1 pandemic. As humans expand further into previously uninhabited areas, likelihood new zoonotic retroviral exposures increases. The role innate immune system, including ISGs, in controlling infections currently an area intensive study. This work provides evidence primed system effective defense against pathogenesis, resulting reduced viral replication and...
Abstract RNA viruses are a major source of emerging and re-emerging infectious diseases around the world. We developed method to identify that is based on fact all produce dsRNA while replicating. Purifying sequencing from total isolated infected tissue allowed us recover replicating viral sequences. refer this approach as dsRNA-Seq. By assembling sequences into contigs we identified full length varying genome types infecting mammalian culture samples, known disease agent in laboratory mice,...
AbstractThis article relates findings from behavioral sciences studies to TA concepts. Specifically, conflict management styles and outcomes are integrated into a “global grid” which facilitates quick learning in training situations. It incorporates ideas some of the earlier writings about “OK Corral” explains inconsistencies that explanation may have been observed by practitioners. Additional informationNotes on contributorsJames H. MorrisonJames Harris Morrison, RM, MA, is psychologist...
Pathogen-associated molecular patterns (e.g., dsRNA) activate expression of IFN-stimulated genes (ISGs), which protect hosts from infection. Although transient ISG upregulation is essential for effective innate immunity, constitutive activation typically causes harmful autoimmunity in mice and humans, often including severe developmental abnormalities. We have shown that transgenic expressing a picornavirus RNA-dependent RNA polymerase (RdRP) outside the viral context (RdRP mice) exhibit...
ABSTRACT The COVID-19 pandemic demonstrated the poor ability of body temperature to reliably identify SARS-CoV-2-infected individuals, an observation that has been made before in context other infectious diseases. While acute infection does not always cause fever, it drive host transcriptional responses as responds at site infection. These changes can occur both cells are directly harboring replicating pathogens and elsewhere receive a molecular signal is occurring. Here, we core set...