A5055046444- HIV Research and Treatment
- interferon and immune responses
- Immune Cell Function and Interaction
- Cytomegalovirus and herpesvirus research
- Signaling Pathways in Disease
- Herpesvirus Infections and Treatments
- SARS-CoV-2 and COVID-19 Research
- HIV/AIDS drug development and treatment
- Virus-based gene therapy research
- RNA Research and Splicing
- COVID-19 Clinical Research Studies
- RNA Interference and Gene Delivery
- Virology and Viral Diseases
- Mosquito-borne diseases and control
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- HIV/AIDS Research and Interventions
- Immunotherapy and Immune Responses
- Viral Infections and Outbreaks Research
- vaccines and immunoinformatics approaches
- Peptidase Inhibition and Analysis
- RNA regulation and disease
- Immune Response and Inflammation
- Bacteriophages and microbial interactions
- RNA modifications and cancer
University College London
2016-2025
Institute of Infection and Immunity
2009-2024
University of California, San Francisco
2023
University of San Francisco
2022
Centre for Immunity, Infection and Evolution
2017
Medical Research Council
2008-2015
MRC Laboratory for Molecular Cell Biology
2009-2014
UCL Australia
2011
The Royal Free Hospital
2005-2009
Columbia University
2002-2003
Antibodies provide effective antiviral immunity despite the fact that viruses escape into cells when they infect. Here we show antibodies remain attached to after cell infection and mediate an intracellular immune response disables virions in cytosol. We have discovered possess a cytosolic IgG receptor, tripartite motif-containing 21 (TRIM21), which binds with higher affinity than any other receptor human body. TRIM21 rapidly recruits incoming antibody-bound virus targets it proteasome via...
Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified an co-factor in previous studies. Here we report that capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion (Cyp) tripartite motif TRIM5 created a novel inhibitor replication, consistent with interaction vivo. In contrast CypA binding CA, Nup358 insensitive...
The emergence of SARS-CoV-2 variants concern suggests viral adaptation to enhance human-to-human transmission
The HIV-1 genome enters cells inside a shell comprised of capsid (CA) protein. Variation in CA sequence alters infectivity and escape from host restriction factors. However, apart the Cyclophilin A-binding loop, has no known interfaces with which to interact cellular cofactors. Here we describe novel protein-protein interface N-terminal domain CA, determined by X-ray crystallography, mediates both viral cofactor dependence. is highly conserved across lentiviruses accessible context hexameric...
ABSTRACT Tripartite motif (TRIM) protein superfamily members are emerging as important effectors of the innate immune response against viral infections. In particular, TRIM22 was reported to exert antiviral activity RNA viruses, such hepatitis B virus (HBV), encephalomyocarditis (ECMV), and human immunodeficiency type 1 (HIV-1). We demonstrate here, for first time, that is upregulated by influenza A (IAV) infection at both mRNA levels in alveolar epithelial A549 cells. Conversely, potently...
Abstract Emergence of SARS-CoV-2 variants, including the globally successful B.1.1.7 lineage, suggests viral adaptations to host selective pressures resulting in more efficient transmission. Although much effort has focused on Spike adaptation for entry and adaptive immune escape, mutations outside likely contribute enhance Here we used unbiased abundance proteomics, phosphoproteomics, mRNA sequencing replication assays show that isolates effectively suppress innate responses airway...
Certain infectious agents are recognised causes of cancer and other chronic diseases. To understand the pathological mechanisms underlying such relationships, here we design a Multiplex Serology platform to measure quantitative antibody responses against 45 antigens from 20 including human herpes, hepatitis, polyoma, papilloma, retroviruses, as well Chlamydia trachomatis, Helicobacter pylori Toxoplasma gondii, then assayed random subset 9695 UK Biobank participants. We find seroprevalence...
Abstract HIV can infect non-dividing cells because the viral capsid overcome selective barrier of nuclear pore complex and deliver genome directly into nucleus 1,2 . Remarkably, intact is more than 1,000 times larger size limit prescribed by diffusion 3 This in central channel composed intrinsically disordered nucleoporin domains enriched phenylalanine–glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins their bound cargoes solubilize this phase to drive...
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human adaptation resulted in distinct lineages with enhanced transmissibility called variants of concern (VOCs). Omicron is the first VOC to evolve globally dominant subvariants. Here we compared their replication cell lines and primary airway cultures measured host responses infection. We discovered that subvariants BA.4 BA.5 have improved suppression innate immunity when earlier BA.1 BA.2. Similarly, more recent (BA.2.75...
The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved medical use. Here, we investigate effect of lenacapavir on HIV stability and uncoating. We employ single particle approach that simultaneously measures content release lattice persistence. demonstrate lenacapavir's potent antiviral activity predominantly due to lethal hyperstabilisation resultant loss compartmentalisation. This...
The rhesus macaque tripartite motif containing protein TRIM5α specifically restricts HIV-1 infection at an early post-entry step before reverse transcription [Stremlau, M., Owens, C. Perron, M. J., Kiessling, Autissier, P. & Sodroski, J. (2004) Nature 427, 848–853]. Here, we show that the human and African green monkey (AGM) genes encode Ref1 Lv1 antiretroviral activities, respectively. Expression of in permissive cat cells renders them resistant to restriction-sensitive murine leukemia...
Retroviruses are able to cross species barriers and have done so many times throughout evolution. Perhaps as a consequence, dominant mechanisms arisen block infection by murine retroviruses in mice (restriction factor Fv1) humans Ref1), well other mammals. Here we describe HIV simian immunodeficiency virus monkeys. Like previously described restrictions the is saturable gives rise multiple-hit kinetics. Furthermore, like restriction of leukemia humans, before reverse transcription....
The murine Fv1 gene restricts infection by N- or B-tropic leukemia viruses at a postentry, preintegration stage. Fv1- sensitive previously used for the study of encode an ecotropic envelope and thus only infect rodent cells. Consequently, restriction has been carried out solely in mice cell lines. By with retroviral vectors containing core pantropic vesicular stomatitis virus-G protein, we now demonstrate that lines derived from various mammalian species, including humans, have -like...
The antiretroviral restriction factor TRIM5 has recently emerged as an important mediator of innate immunity and species-specific inhibition retroviral replication in mammals. Selection pressure from pathogenic infection driven rapid evolution genes, leading to the antiviral specificities we see today. Remarkably, New World owl monkey ( Aotus trivirgatus ) encodes a protein which determinants B30.2 domain have been replaced by cyclophilin A (CypA) encoded retrotransposed cDNA. TRIMCyp...
Genome-wide siRNA screens have identified host cell factors important for efficient HIV infection, among which are nuclear pore proteins such as RanBP2/Nup358 and the karyopherin Transportin-3/TNPO3. Analysis of roles these in replication cycle suggested that correct trafficking through may facilitate subsequent integration step. Here we present data coupling between steps by demonstrating depletion Transportin-3 or RanBP2 altered terminal step early replication, selection chromosomal sites...
The recently identified restriction factor tetherin/BST-2/CD317 is an interferon-inducible trans-membrane protein that restricts HIV-1 particle release in the absence of countermeasure viral U (Vpu). It known Tantalus monkey CV1 cells can be rendered non-permissive to upon stimulation with type 1 interferon, despite presence Vpu, suggesting species-specific sensitivity tetherin proteins countermeasures such as Vpu. Here we demonstrate by nearly two orders magnitude, but contrast human...
The HIV capsid is semipermeable and covered in electropositive pores that are essential for viral DNA synthesis infection. Here, we show these bind the abundant cellular polyanion IP6, transforming stability from minutes to hours allowing newly synthesised accumulate inside capsid. An arginine ring within pore coordinates which strengthens hexamers by almost 10°C. Single molecule measurements demonstrate this renders native capsids highly stable protected spontaneous collapse. Moreover,...