A5014650300- HIV Research and Treatment
- SARS-CoV-2 and COVID-19 Research
- Animal Virus Infections Studies
- Immune Cell Function and Interaction
- COVID-19 Clinical Research Studies
- Monoclonal and Polyclonal Antibodies Research
- HIV/AIDS drug development and treatment
- T-cell and B-cell Immunology
- CRISPR and Genetic Engineering
- RNA Interference and Gene Delivery
- Glycosylation and Glycoproteins Research
- CAR-T cell therapy research
- Influenza Virus Research Studies
- interferon and immune responses
- Viral Infections and Immunology Research
- Antimicrobial Peptides and Activities
- Viral gastroenteritis research and epidemiology
- Virus-based gene therapy research
- Computational Drug Discovery Methods
- SARS-CoV-2 detection and testing
- Canadian Policy and Governance
- Tryptophan and brain disorders
- Metabolomics and Mass Spectrometry Studies
- Bacteriophages and microbial interactions
- Music History and Culture
Scripps Research Institute
2013-2024
University of Florida
2023-2024
Broad Institute
2023
University of Pennsylvania
2023
Jackson Memorial Hospital
2023
Boston Children's Museum
2023
Boston Children's Hospital
2023
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2023
Stanford University
2023
Jupiter Medical Center
2023
SARS-CoV-2 variants with spike (S)-protein D614G mutations now predominate globally. We therefore compare the properties of mutated S protein (SG614) original (SD614). report here pseudoviruses carrying SG614 enter ACE2-expressing cells more efficiently than those SD614. This increased entry correlates less S1-domain shedding and higher S-protein incorporation into virion. Similar results are obtained virus-like particles produced M, N, E, proteins. However, does not alter binding to ACE2 or...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme (ACE2). ACE2 is also the viral receptor SARS-CoV (SARS-CoV-1), a related that emerged in 2002–2003. Horseshoe bats (genus Rhinolophus ) are presumed to be original reservoir both viruses, and SARS-like coronavirus, RaTG13, closely SARS-CoV-2, has been identified one horseshoe-bat species. Here we characterize ability S-protein...
Abstract During the COVID-19 pandemic, Pfizer-BioNTech and Moderna successfully developed nucleoside-modified mRNA lipid nanoparticle (LNP) vaccines. SARS-CoV-2 spike protein expressed by those vaccines are identical in amino acid sequence, but several key components distinct. Here, we compared effect of ionizable lipids, untranslated regions (UTRs), nucleotide composition two vaccines, focusing on delivery, antibody generation, long-term stability. We found that lipid, SM-102, Moderna’s...
Members of the TRIpartite interaction Motif (TRIM) family E3 ligases have been shown to exhibit antiviral activities. Here we report a near comprehensive screen for antiretroviral activities 55 TRIM proteins (36 human, 19 mouse). We identified ∼20 that, when transiently expressed in HEK293 cells, affect entry or release human immunodeficiency virus 1 (HIV), murine leukemia (MLV), avian leukosis (ALV). While TRIM11 and 31 inhibited HIV entry, enhanced N-MLV by interfering with Ref1...
SUMMARY The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates entry of SARS-CoV-2 into cells expressing the angiotensin-converting enzyme (ACE2). S engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment 1273-amino S-protein protomer. Antibodies to RBD SARS-CoV (SARS-CoV-1), a closely related coronavirus which emerged in 2002-2003, have been shown potently neutralize SARS-CoV-1 S-protein-mediated entry, and presence anti-RBD antibodies...
The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates entry of SARS-CoV-2 into cells expressing the angiotensin-converting enzyme (ACE2). S engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment 1273-amino S-protein protomer. Antibodies to RBD SARS-CoV (SARS-CoV-1), a closely related coronavirus which emerged in 2002-2003, have been shown potently neutralize SARS-CoV-1 S-protein-mediated entry, and presence anti-RBD antibodies...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme (ACE2). ACE2 is also the viral receptor SARS-CoV (SARS-CoV-1), a related that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus ) are presumed to be original reservoir both viruses, and SARS-like coronavirus, RaTG13, closely SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize ability S-protein...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates viral entry into cells expressing angiotensin-converting enzyme (ACE2). S engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino-acid fragment of the 1,273-amino-acid S-protein protomer. RBD is primary SARS-CoV-2 neutralizing epitope and a critical target any vaccine. Here, we show that this conjugated to each two carrier proteins elicited more potent responses in...
A tyrosine-sulfated CCR5-mimetic peptide, CCR5mim1, inhibits HIV-1 infection more efficiently than sulfopeptides based on the CCR5 amino terminus. Here we characterized sulfopeptide chimeras of CCR5mim1 and heavy-chain CDR3 antibody PG16. Two bound a range envelope glycoproteins neutralized CCR5mim1. An immunoadhesin form one these, CCR5mim2-Ig, synergized with CD4-Ig to neutralize HIV-1. These are among broadest most potent peptides described date.
Many broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus type 1 (HIV-1) were shown effective in animal models, and are currently evaluated clinical trials. However, use of these humans is hampered by the rapid emergence resistant viruses. Here we show that soft-randomization can be used to accelerate parallel identification viral escape pathways. As a proof principle, soft-randomized epitope regions VRC01-class bNAbs replication-competent HIV-1 selected for variants....
ABSTRACT The HIV-1 envelope glycoprotein is a trimeric complex of heterodimers composed surface glycoprotein, gp120, and transmembrane component, gp41. association this with CD4 stabilizes the coreceptor-binding site gp120 promotes exposure gp41 helical region 1 (HR1). Here, we show that 15-amino-acid peptide mimetic coreceptor CCR5 fused to dimeric antibody Fc domain (CCR5mim-Ig) bound two molecules per by itself promoted HR1 exposure. CCR5mim-Ig also stabilized CD4-mimetic glycoprotein. A...
ABSTRACT The HIV-1 envelope glycoprotein (Env) is a trimer of gp120/gp41 heterodimers that mediates viral entry. Env binds cellular CD4, an association which stabilizes conformation favorable to its subsequent with coreceptor, typically CCR5 or CXCR4. CD4- and coreceptor-binding sites serve as epitopes for two classes HIV-1-neutralizing antibodies: CD4-binding site (CD4bs) CD4-induced (CD4i) antibodies, respectively. Here we observed that, at fixed total concentration, mixtures the CD4i...
B cells have been engineered ex vivo to express an HIV-1 broadly neutralizing antibody (bNAb). cell reprograming may be scientifically and therapeutically useful, but current approaches limit repertoire diversity disrupt the organization of heavy-chain locus. A more diverse physiologic targeting a key epitope could facilitate evaluation vaccines designed elicit bNAbs, help identify potent bioavailable bNAb variants, or directly enhance viral control in vivo. Here we address challenges...
The HIV-1 envelope glycoprotein binds cooperatively to its cellular receptor CD4 and a coreceptor, principally CXCR4 or CCR5. We have previously improved natural amino-acid form of scorpion toxin-derived CD4-mimetic peptide in parallel generated sulfopeptide mimetics the CCR5 amino terminus. Here we show that some fusions these CCR5- peptides, expressed as immunoadhesins, neutralize more efficiently than CD4-Fc equimolar mixtures immunoadhesin forms each peptide. Specifically, double-mimetic...
Significance Broadly neutralizing antibodies (bNAbs) can prevent new HIV-1 infections, but most are insufficiently broad or potent to protect from the diverse pool of circulating viruses. V2-glycan/apex bNAbs exceptionally potent, their breadth is limited. Their activity requires tyrosine sulfation, a posttranslational modification that precludes improvement with phage yeast display. Here, we demonstrate utility mammalian display approach whereby heavy- and light-chain loci B cell line...
Abstract Effective intervention strategies are urgently needed to control the COVID-19 pandemic. Human angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that forms dimer and serves as cellular receptor for SARS-CoV-2. It also key negative regulator of renin-angiotensin system (RAS), conserved in mammals, which modulates vascular functions. We report here properties trimeric ACE2 variant, created by structure-based approach, with binding affinity ~60 pM spike (S) protein...
The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates viral entry into cells expressing the angiotensin-converting enzyme (ACE2). S engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment of 1273-amino S-protein protomer. RBD is primary SARS-CoV-2 neutralizing epitope and a critical target any vaccine. Here we show that this conjugated to each two carrier proteins elicited more potent responses in immunized rodents than did similarly...
Abstract During the COVID-19 pandemic, Pfizer-BioNTech and Moderna successfully developed nucleoside-modified mRNA lipid nanoparticle (LNP) vaccines. SARS-CoV-2 spike protein expressed by those vaccines are identical in amino acid sequence, but several key components distinct. Here, we compared effect of ionizable lipids, untranslated regions (UTRs), nucleotide composition two vaccines, focusing on delivery, antibody generation, long-term stability. We found that lipid, SM-102, Moderna’s...
CRISPR-edited murine B cells engineered to express human antibody variable chains proliferate, class switch, and secrete these antibodies in vaccinated mice. However, current strategies disrupt the heavy-chain locus, resulting inefficient somatic hypermutation without functional affinity maturation. Here we show that recombined heavy- kappa-variable genes can be directly simultaneously overwritten, using Cas12a-mediated cuts at their 3'-most J segments 5' homology arms complementary distal V...
Abstract B cells have been engineered ex vivo to express an HIV-1 broadly neutralizing antibody (bNAb). B-cell reprograming may be scientifically and therapeutically useful, but current approaches limit repertoire diversity disrupt the organization of heavy-chain locus. A more diverse physiologic targeting a key epitope could facilitate evaluation vaccines designed elicit bNAbs, help identity potent bioavailable bNAb variants, or directly enhance viral control in . Here we address challenges...