ORCID Profile
0000-0001-7077-6793
Current Organisation
University of Oxford
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Publisher: Oxford University Press (OUP)
Date: 27-02-2020
DOI: 10.1093/JAC/DKAA033
Abstract: HIV-1 integrase inhibitors are recommended as first-line therapy by WHO, though efficacy and resistance data for non-B subtypes are limited. Two recent trials have identified the integrase L74I mutation to be associated with integrase inhibitor treatment failure in HIV-1 non-B subtypes. We sought to define the prevalence of integrase resistance mutations, including L74I, in West Africa. We studied a Nigerian cohort of recipients prior to and during receipt of second-line PI-based therapy, who were integrase inhibitor-naive. Illumina next-generation sequencing with target enrichment was used on stored plasma s les. Drug resistance was interpreted using the Stanford Resistance Database and the IAS-USA 2019 mutation lists. Of 115 in iduals, 59.1% harboured CRF02_AG HIV-1 and 40.9% harboured subtype G HIV-1. Four participants had major IAS-USA integrase resistance-associated mutations detected at low levels (2%–5% frequency). Two had Q148K minority variants and two had R263K (one of whom also had L74I). L74I was detected in plasma s les at over 2% frequency in 40% (46/115). Twelve (26.1%) had low-level minority variants of between 2% and 20% of the viral population s led. The remaining 34 (73.9%) had L74I present at & % frequency. L74I was more common among those with subtype G infection (55.3%, 26/47) than those with CRF02_AG infection (29.4%, 20/68) (P = 0.005). HIV-1 subtypes circulating in West Africa appear to have very low prevalence of major integrase mutations, but significant prevalence of L74I. A combination of in vitro and clinical studies is warranted to understand the potential implications.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2021
DOI: 10.1038/S41586-021-03944-Y
Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha) 1 . In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered in iduals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2021
Publisher: Cold Spring Harbor Laboratory
Date: 05-12-2019
DOI: 10.1101/865840
Abstract: Protease Inhibitors (PIs) are the second- and last-line therapy for the majority of HIV-infected patients worldwide. Only around 20% of in iduals who fail PI regimens develop major resistance mutations in protease. We sought to explore the role of mutations in gag-protease genotypic and phenotypic changes within six Nigerian patients who failed PI-based regimens without known drug resistance associated protease mutations in order to identify novel determinants of PI resistance. Target enrichment and NGS by Illumina Miseq were followed by haplotype reconstruction. Full length gag -protease regions were lified from baseline (pre-PI) and virologic failure (VF) s les, sequenced and used to construct gag / protease pseudotyped viruses. Phylogenetic analysis was performed using maximum likelihood methods. Susceptibility to lopinavir (LPV) and darunavir (DRV) were measured using a single-cycle replication assay. Western blotting was used to analyse Gag cleavage. In one of six participants (subtype CRF02_AG) we found 4-fold lower LPV susceptibility in viral clones during failure of second line treatment. A combination of four mutations (S126del, H127del, T122A and G123E) in p17 matrix of baseline virus generated a similar 4x decrease in susceptibility to LPV but not darunavir. These four amino acid changes were also able to confer LPV resistance to a subtype B gag-protease backbone. Western blotting did not demonstrate significant Gag cleavage differences between sensitive and resistant isolates. Resistant viruses had around 2-fold lower infectivity compared to sensitive clones in the absence of drug. NGS combined with haplotype reconstruction revealed resistant, less fit clones emerged from a minority population at baseline and thereafter persisted alongside sensitive fitter viruses. We have used a multi-pronged genotypic and phenotypic approach to document emergence and temporal dynamics of a novel protease inhibitor resistance signature in p17 matrix, revealing the interplay between Gag associated resistance and fitness.
Publisher: American Society for Microbiology
Date: 22-12-2020
Abstract: Protease inhibitors (PIs) are the second- and last-line therapy for the majority of HIV-infected patients worldwide. Only around 20% of in iduals who fail PI regimens develop major resistance mutations in protease. We sought to explore the role of mutations in gag - pro genotypic and phenotypic changes in viruses from six Nigerian patients who failed PI-based regimens without known drug resistance-associated protease mutations in order to identify novel determinants of PI resistance.
Publisher: Springer Science and Business Media LLC
Date: 21-07-2022
Publisher: Springer Science and Business Media LLC
Date: 21-07-2022
Publisher: Springer Science and Business Media LLC
Date: 11-03-2021
DOI: 10.1038/S41586-021-03412-7
Abstract: Transmission of SARS-CoV-2 is uncontrolled in many parts of the world control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant
Publisher: Elsevier BV
Date: 08-2023
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Steven Kemp.