A5043025715- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- SARS-CoV-2 and COVID-19 Research
- Cytomegalovirus and herpesvirus research
- Virus-based gene therapy research
- COVID-19 Clinical Research Studies
- CRISPR and Genetic Engineering
- SARS-CoV-2 detection and testing
- Virology and Viral Diseases
- Long-Term Effects of COVID-19
- Animal Virus Infections Studies
- Enzyme Structure and Function
- Protein purification and stability
- Viral-associated cancers and disorders
- Plant Virus Research Studies
- RNA Research and Splicing
- T-cell and Retrovirus Studies
- Neonatal Health and Biochemistry
- RNA modifications and cancer
- Yersinia bacterium, plague, ectoparasites research
- Pancreatic function and diabetes
- Bacteriophages and microbial interactions
- Nuclear Structure and Function
- HIV/AIDS Research and Interventions
The Francis Crick Institute
2016-2025
Imperial College London
2014-2024
St Mary's Hospital
2020-2023
University College London Hospitals NHS Foundation Trust
2020
University College London
2020
National Hospital for Neurology and Neurosurgery
2020
University Hospital Carl Gustav Carus
2016
Technische Universität Dresden
2016
Chromosome 18 Registry & Research Society
2016
Institute for Molecular Medicine
2016
Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected humoral immunity. spike glycoprotein (S)-reactive were detectable using a flow cytometry-based method SARS-CoV-2-uninfected individuals and particularly prevalent children adolescents. They predominantly the immunoglobulin G (IgG) class targeted S2 subunit. By contrast, infection induced higher titers S-reactive IgG...
We have reported that human immunodeficiency virus type 1 (HIV-1) integrase (IN) forms a specific nuclear complex with lens epithelium-derived growth factor/transcription co-activator p75 (LEDGF/p75) protein. now studied the IN-LEDGF/p75 interaction and import of IN in living cells using fusions LEDGF/p75 enhanced green fluorescent protein far-red HcRed1. show both N-terminal zinc binding domain central core domains are involved LEDGF/p75. Both essential for localization as well association...
LEDGF/p75 directly interacts with lentiviral integrase proteins and can modulate their enzymatic activities chromosomal association. A novel genetic knockout model was established that allowed us for the first time to analyze HIV-1 integration in absence of protein. Supporting a crucial role cofactor viral replication, vector reporter gene expression were significantly reduced LEDGF-null cells. Yet, processed cDNA termini normally maintained its local target DNA sequence preference during...
Integrase (IN) is an essential retroviral enzyme, and human transcriptional coactivator p75, which also referred to as lens epithelium-derived growth factor (LEDGF), the dominant cellular binding partner of HIV-1 IN. Here, we report crystal structure dimeric catalytic core domain IN complexed IN-binding LEDGF. Previously identified LEDGF hotspot residues anchor protein both monomers at dimer interface. The principal structural features that are recognized by host backbone conformation...
The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding viral resistance to these molecules have been hampered by a paucity available structural data. We recently reported cocrystal structures the prototype foamy virus (PFV) intasome with raltegravir elvitegravir, establishing general INSTI binding mode. now present an expanded set containing PFV intasomes complexed first- second-generation INSTIs at resolutions up 2.5 Å. Importantly, improved...
Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro suppress viremia patients. These small molecules bind to the IN active site, causing it disengage from deoxyadenosine at 3′ end of DNA. The emergence strains that are highly resistant RAL underscores pressing need develop INSTIs with improved resistance profiles. Herein, we show candidate second-generation drug dolutegravir (DTG, S/GSK1349572) effectively...
Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines show protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, spike. Because new SARS-CoV-2 variants are emerging rapidly, as exemplified B.1.1.7, B.1.351, and P.1 lineages, it critical to understand whether antibody responses induced infection with original virus or current remain effective. In this study, we evaluate neutralization of a series mutated...
Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants novel antigenic profiles threatens diminish their efficacy. Assessment ability sera from vaccine recipients neutralise will inform success strategies for minimising COVID19 cases design formulations. Here, we examine sensitivity concern (VOCs) representative B.1.617.1 B.1.617.2 (first infections India) B.1.351 South Africa) lineages...
Accurate antibody tests are essential to monitor the SARS-CoV-2 pandemic. Lateral flow immunoassays (LFIAs) can deliver testing at scale. However, reported performance varies, and sensitivity analyses have generally been conducted on serum from hospitalised patients. For use in community testing, evaluation of finger-prick self-tests, non-hospitalised individuals, is required.Sensitivity analysis was 276 participants. All had tested positive for by reverse transcription PCR were ≥21 days...
Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with ACE2 on host cells is essential for viral entry. RBD dominant target neutralizing antibodies, and several epitopes have been molecularly characterized. Analysis circulating variants has revealed mutations arising in RBD, N-terminal (NTD) S2 subunits Spike. To understand how these affect antigenicity, we isolated characterized >100 monoclonal antibodies targeting NTD, from SARS-CoV-2-infected individuals. Approximately 45%...
SARS-CoV-2 spike N-terminal domain harbors a potent epitope that can be modulated by binding of natural linear tetrapyrroles.
SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, lysosomal transmembrane protein, can serve as an alternative receptor for into angiotensin-converting enzyme 2 (ACE2)-negative Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked infection, demonstrating role in viral Using X-ray...
ATG9A and ATG2A are essential core members of the autophagy machinery. is a lipid scramblase that allows equilibration lipids across membrane bilayer, whereas facilitates flow between tethered membranes. Although both have been functionally linked during formation autophagosomes, molecular details consequences their interaction remain unclear. By combining data from peptide arrays, crosslinking, hydrogen-deuterium exchange mass spectrometry together with cryoelectron microscopy, we propose...
Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with spike glycoproteins (S) diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such responses, typically targeting conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we...
Transmission by flea bite is a relatively recent adaptation that distinguishes Yersinia pestis, the plague bacillus, from closely related enteric bacteria. Here, plasmid-encoded phospholipase D (PLD), previously characterized as murine toxin (Ymt), was shown to be required for survival of Y. pestis in midgut its principal vector, rat Xenopsylla cheopis. Intracellular PLD activity appeared protect cytotoxic digestion product blood plasma gut. By enabling colonization midgut, acquisition this...
Human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) protein was recently identified as a binding partner for HIV-1 integrase (IN) in human cells. In this work, we used biochemical and bioinformatic approaches to define the domain organization of LEDGF/p75. Using limited proteolysis deletion mutagenesis show that contains pair evolutionarily conserved domains, assuming about 35% its sequence. Whereas N-terminal PWWP had been recognized previously, second...