A5020713269- interferon and immune responses
- HIV Research and Treatment
- RNA Research and Splicing
- RNA regulation and disease
- Viral Infections and Immunology Research
- SARS-CoV-2 and COVID-19 Research
- RNA and protein synthesis mechanisms
- Chromosomal and Genetic Variations
- CRISPR and Genetic Engineering
- Immune Response and Inflammation
- Cytomegalovirus and herpesvirus research
- Virus-based gene therapy research
- Genomics and Phylogenetic Studies
- RNA modifications and cancer
- Herpesvirus Infections and Treatments
- COVID-19 Clinical Research Studies
- HIV/AIDS drug development and treatment
- Sepsis Diagnosis and Treatment
- Nuclear Structure and Function
- Viral Infections and Vectors
- Phagocytosis and Immune Regulation
- Toxoplasma gondii Research Studies
- Viral Infections and Outbreaks Research
- T-cell and B-cell Immunology
- RNA Interference and Gene Delivery
King's College London
2015-2025
Guy's Hospital
2006-2020
King's College School
2004-2013
University of Pennsylvania
2004
The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 -2) requires sequential protease processing the viral spike glycoprotein. presence a polybasic cleavage site in SARS-CoV-2 at S1/S2 boundary has been suggested to be factor increased transmissibility compared SARS-CoV-1 by facilitating maturation precursor furin-like proteases producer cells rather than endosomal cathepsins target. We investigate relevance route consequences this for...
ABSTRACT Members of the APOBEC ( apo lipoprotein B mRNA- e diting enzyme c atalytic polypeptide 1-like) family cytidine deaminases inhibit host cell genome invasion by exogenous retroviruses and endogenous retrotransposons. Because these enzymes can edit DNA or RNA potentially mutate cellular targets, their activities are presumably regulated; for instance, APOBEC3G (A3G) recruitment into high-molecular-weight ribonucleoprotein (RNP) complexes has been shown to suppress its enzymatic...
Recent evidence shows that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sensitive to interferons (IFNs). However, the most effective types of IFNs and underlying antiviral effectors remain be defined. Here, we show zinc finger protein (ZAP), which preferentially targets CpG dinucleotides in viral RNA sequences, restricts SARS-CoV-2. We further demonstrate ZAP its cofactors KHNYN TRIM25 are expressed human lung cells. Type I, II, III all strongly inhibited SARS-CoV-2...
CpG dinucleotides are suppressed in most vertebrate RNA viruses, including HIV-1, and introducing CpGs into virus genomes inhibits their replication. The zinc finger antiviral protein (ZAP) binds regions of viral containing targets them for degradation. ZAP does not have enzymatic activity recruits other cellular proteins to inhibit We found that KHNYN, a with no previously known function, interacts ZAP. KHNYN overexpression selectively HIV-1 clustered this requires its cofactor TRIM25. both...
Sepsis is life-threatening organ dysfunction due to dysregulated host responses infection. Current knowledge of human B-cell alterations in sepsis sparse. We tested the hypothesis that loss involves distinct subpopulations B cells and investigated mechanisms depletion.Prospective cohort study.Critical care units.Adult patients without any documented immune comorbidity.None.B-cell subsets were quantified by flow cytometry; annexin-V status identified apoptotic phosphorylation intracellular...
The appearance of new dominant variants concern (VOC) severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) threatens the global response to disease 2019 (COVID-19) pandemic. Of these, alpha variant (also known as B.1.1.7), which appeared initially in United Kingdom, became much Europe and North America first half 2021. spike (S) glycoprotein acquired seven mutations two deletions compared ancestral virus, including P681H mutation adjacent polybasic cleavage site, has been...
Abstract Background The identification of cellular factors that regulate the replication exogenous viruses and endogenous mobile elements provides fundamental understanding host-pathogen relationships. MOV10 is a superfamily 1 putative RNA helicase controls several whose homologs are necessary for repression elements. Here, we employ both ectopic expression gene knockdown approaches to analyse role human in panel retroviruses retroelements. Results overexpression substantially decreased...
The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins are cell-encoded cytidine deaminases, some of which, such as APOBEC3G (A3G) and APOBEC3F (A3F), act potent human immunodeficiency virus type-1 (HIV-1) restriction factors. These require packaging into HIV-1 particles to exert their antiviral activities, but the molecular mechanism by which this occurs is incompletely understood. nucleocapsid (NC) region Gag required for efficient incorporation A3G A3F,...
CpG dinucleotides are suppressed in the genomes of many vertebrate RNA viruses, including HIV-1. The cellular antiviral protein ZAP (zinc finger protein) binds CpGs and inhibits HIV-1 replication when introduced into viral genome. However, it is not known if ZAP-mediated restriction only mechanism driving suppression. To determine how affect replication, we increased their abundance multiple regions genome analyzed effect on expression, abundance, infectious-virus production. We found that...
The zinc finger antiviral protein (ZAP) restricts the replication of a broad range RNA and DNA viruses. ZAP directly binds viral RNA, targeting it for degradation inhibiting its translation. While full scope determinants involved in mediating selective activity is unclear, CpG dinucleotides, dictating at least part target specificity. interacts with many cellular proteins, although only few have been demonstrated to be essential activity, including 3'-5' exoribonuclease exosome complex,...
Ebola virus (EBOV) causes highly pathogenic disease in primates. Through screening a library of human interferon-stimulated genes (ISGs), we identified TRIM25 as potent inhibitor EBOV transcription-and-replication-competent virus-like particle (trVLP) propagation. overexpression inhibited the accumulation viral genomic and messenger RNAs independently RNA sensor RIG-I or secondary proinflammatory gene expression. Deletion strongly attenuated sensitivity trVLPs to inhibition by type-I...
The human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3F (APOBEC3F [A3F]) and A3G proteins are effective inhibitors of infection by various retroelements share approximately 50% amino acid sequence identity. We therefore undertook comparative analyses the protein RNA compositions A3F- A3G-associated ribonucleoprotein complexes (RNPs). Like A3G, A3F is found associated with a complex array cytoplasmic RNPs can accumulate in RNA-rich microdomains known as mRNA processing...
Retroviruses encode cis-acting RNA nuclear export elements that override retention of intron-containing viral mRNAs including the full-length, unspliced genomic RNAs (gRNAs) packaged into assembling virions. The HIV-1 Rev-response element (RRE) recruits cellular receptor CRM1 (also known as exportin-1/XPO1) using protein Rev, while simple retroviruses constitutive transport (CTEs) directly recruit components NXF1(Tap)/NXT1(p15) mRNA machinery. How gRNA is linked to trafficking machineries in...
Environmental changes induce human NKG2D ligand expression—immunological visibility—through the EGFR stress response.
The zinc finger antiviral protein (ZAP) is a broad inhibitor of virus replication. Its best-characterized function to bind CpG dinucleotides present in viral RNAs and, through the recruitment TRIM25, KHNYN and other cofactors, target them for degradation or prevent their translation. long short isoforms ZAP (ZAP-L ZAP-S) have different intracellular localization it unclear how this regulates activity against viruses with sites Using ZAP-sensitive ZAP-insensitive human immunodeficiency type I...
ABSTRACT Nuclear RNA processing events, such as 5′ cap formation, 3′ polyadenylation, and pre-mRNA splicing, mark mRNA for efficient translation. Splicing enhances translation via the deposition of exon-junction complex other multifunctional splicing factors, including SR proteins. All retroviruses synthesize their structural enzymatic proteins from unspliced genomic RNAs (gRNAs) must therefore exploit unconventional strategies to ensure effective expression. Here, we report that specific...
The APOBEC3 cytidine deaminases play a critical role in host-mediated defense against exogenous viruses, most notably, human immunodeficiency virus type-1 (HIV-1) and endogenous transposable elements. APOBEC3G APOBEC3F interact with numerous proteins that regulate cellular RNA metabolism, including components of the RNA-induced silencing complex (RISC), colocalize subset these to mRNA processing bodies (P bodies), which are sites translational repression decay. We sought determine P...
Primate lentivirus Vif proteins function by suppressing the antiviral activity of cell-encoded apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC) APOBEC3G and APOBEC3F. It has been hypothesized that species-specific susceptibilities APOBEC to may help govern transmission primate lentiviruses new host species. Consistent with this view previous results, we report several diverse simian immunodeficiency viruses (SIVs) are not known infect humans effective inhibitors human...
The human immunodeficiency virus type 1 (HIV-1) structural protein Gag is necessary and sufficient to form viral particles. In addition encoding the amino acid sequence for Gag, underlying RNA could encode cis-acting elements or nucleotide biases that are replication. Furthermore, sequences inhibit replication be suppressed in gag. However, functional relevance of promote repress HIV-1 remain poorly understood. To characterize if gag controls replication, matrix (MA) region was codon...
SUMMARY Variants of concern (VOCs) severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) threaten the global response to COVID-19 pandemic. The alpha (B.1.1.7) variant appeared in UK became dominant Europe and North America early 2021. Spike glycoprotein has acquired a number mutations including P681H mutation polybasic cleavage site that been suggested enhance cleavage. Here, we show protein confers level resistance effects interferon-β (IFNβ) lung epithelial cells. This...
Human immunodeficiency virus type 1 (HIV-1) assembles poorly in murine cells, reflecting inefficient targeting of the Gag structural polyprotein to plasma membrane. Virus particle production can be restored by replacing cis-acting Rev response element (RRE) Gag-Pol mRNAs with multiple copies CTE (4xCTE), suggesting a mechanistic link between HIV-1 RNA trafficking and productive assembly. In this report, we demonstrate that molecules generated from RRE-dependent transcripts are intrinsically...