Research
We focus on the structural analysis of packaging signals in mammalian retroviruses and rotaviruses. We have identified packaging signals in HIV-1, HIV-2 and SIV and have two and three-dimensional structure of varying parts of these. We also use single molecule FRET and new SHAPE technology to derive three dimensional structures of these RNAs and determine RNA/RNA and RNA protein interactions. We were the first to demonstrate cotranslational packaging in HIV-2, since confirmed in HIV-1. We also identified critical differences in RNA packaging between the closely related HIV-1 and HIV-2, both of which are causative agents of AIDS. We have recently been awarded a Milstein grant from the MRC developing an assay for a high throughput screen to look for novel therapies against HIV targeting the packaging process. In a recent collaboration with Dept Surgery we've been trying to deliver genes which optimise organ transplantation and reduce allograft rejection.
Publications
HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Gupta RK, Abdul-Jawad S, McCoy LE, Mok HP, Salgado DPM, Martinez-Picado J, Nijhuis M, Wensing AMJ, Lee H, Grant P, Nastouli E, Lambert J, Pace M, Salasc F, Monit C, Innes, Mui L, Waters L, Frater J, Lever AML, Edwards SG, Gabriel IH, Olavarria E. Nature 2019 Apr;568 (7751):244-248
A new method for detecting signal regions in ordered sequences of real numbers, and application to viral genomic data. Gog JR, Lever AML, Skittrall JP PLoS One, 2018; 13(4)
No evidence of ongoing evolution in replication competent latent HIV-1 in a patient followed up for two years. Mok HP, Norton NJ, Hirst JC, Fun A, Bandara M, Wills MR, Lever AML Sci Rep,2018; 8(1), 2639
DDX17 Specifically, and independently of DDX5, controls use of the HIV A4/5 splice acceptor cluster and is essential for efficient replication of HIV. Sithole N, Williams CA, Vaughan AM, Kenyon JC, Lever AML J Mol Biol. 2018 Sep 14;430, 3111-3128
Persistence of imported Malaria into the UK: an epidemiological review of risk factors and at risk groups Moyo QM, Besser M, Lynn R Lever AML Clinical Infectious Diseases
Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans-Splicing Induces Selective Killing of HIV-Producing Cells. Ingemarsdotter CK, Poddar S, Mercier S, Patzel V, Lever AML. Mol Ther Nucleic Acids. 2017 Jun 16;7:140-154.
A highly reproducible quantitative viral outgrowth assay for the measurement of the replication-competent latent HIV-1 reservoir. Fun A, Mok HP, Wills MR, Lever AM. Sci Rep. 2017 Feb 24;7:43231
Innovations in the quantitative virus outgrowth assay and its use in clinical trials. Norton NJ, Fun A, Bandara M, Wills MR, Mok HP, Lever AML. Retrovirology. 2017 Dec 21;14(1):58.
Coordination of Genomic RNA Packaging with Viral Assembly in HIV-1. Hellmund C, Lever AM. Viruses. 2016 Jul 14;8(7
Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host. Klemm EJ, Gkrania-Klotsas E, Hadfield J, Forbester JL, Harris SR, Hale C, Heath JN, Wileman T, Clare S, Kane L, Goulding D, Otto TD, Kay S, Doffinger R, Cooke FJ, Carmichael A, Lever AM, Parkhill J, MacLennan CA, Kumararatne D, Dougan G, Kingsley RA. Nat Microbiol. 2016 Mar;1(3). pii: 15023.
Promoter optimisation of lentiviral vectors for efficient insulin gene expression in canine mesenchymal stromal cells: potential surrogate beta cells. Gautam P, Recino A, Foale RD, Zhao J, Gan SU, Wallberg M, Calne R, Lever AM. J Gene Med. 2016 Oct;18(10):312-321.
Coordination of Genomic RNA Packaging with Viral Assembly in HIV-1. Hellmund C, Lever AM. Viruses. 2016 Jul 14;8(7
Characterizing 3D RNA structure by single molecule FRET. Stephenson JD, Kenyon JC, Symmons MF, Lever AM. Methods. 2016 Jul 1;103:57-67.
A novel combined RNA-protein interaction analysis distinguishes HIV-1 Gag protein binding sites from structural change in the viral RNA leader. Kenyon JC, Prestwood LJ, Lever AM. Sci Rep. 2015 Oct 9;5:14369
An RNA-binding compound that stabilizes the HIV-1 gRNA packaging signal structure and specifically blocks HIV-1 RNA encapsidation. Ingemarsdotter CK, Zeng J, Long Z, Lever AML, Kenyon JC Retrovirology. 2018 Mar 14;15(1):25
Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans-Splicing Induces Selective Killing of HIV-Producing Cells. Ingemarsdotter CK, Poddar S, Mercier S, Patzel V, Lever AML. Mol Ther Nucleic Acids. 2017 Jun 16;7:140-154.
Evidence that the endosomal sorting complex required for transport-II (ESCRT-II) is required for efficient human immunodeficiency virus-1 (HIV-1) production. Meng B, Ip NC, Prestwood LJ, Abbink TE, Lever AM. Retrovirology. 2015 Aug 14;12:72.
Identification of RNA helicases in human immunodeficiency virus 1 (HIV-1) replication – a targeted small interfering RNA library screen using pseudotyped and WT HIV-1. Williams CA, Abbink TE, Jeang KT, Lever AM. J Gen Virol. 2015 Jun;96(Pt 6):1484-9
Kenyon JC, Tanner SJ, Legiewicz M, Phillip PS, Rizvi TA, Le Grice SFJ, Lever AM. SHAPE Analysis of the FIV Leader RNA reveals a structural switch potentially controlling Viral Packaging and Genome Dimerization Nucleic Acids Res. 2011 39(15):6692-704
