Imperial College London

Professor Peter Cherepanov

Faculty of MedicineDepartment of Infectious Disease

Professor of Molecular Virology
 
 
 
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Contact

 

p.cherepanov

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

116 results found

Ng KW, Faulkner N, Finsterbusch K, Wu M, Harvey R, Hussain S, Greco M, Liu Y, Kjaer S, Swanton C, Gandhi S, Beale R, Gamblin SJ, Cherepanov P, McCauley J, Daniels R, Howell M, Arase H, Wack A, Bauer DL, Kassiotis Get al., 2022, SARS-CoV-2 S2-targeted vaccination elicits broadly neutralizing antibodies, SCIENCE TRANSLATIONAL MEDICINE, Vol: 14, ISSN: 1946-6234

Journal article

Ijaz S, Dicks S, Jegatheesan K, Parker E, Katsanovskaja K, Vink E, McClure MO, Shute J, Hope J, Cook N, Cherepanov P, Turtle L, Paxton WA, Pollakis G, Ho A, Openshaw PJM, Baillie JK, Semple MG, Tedder RS, for ISARIC4C Investigatorset al., 2022, Mapping of SARS-CoV-2 IgM and IgG in gingival crevicular fluid: antibody dynamics and linkage to severity of COVID-19 in hospital inpatients, Journal of Infection, Vol: 85, Pages: 152-160, ISSN: 0163-4453

Journal article

Ballandras-Colas A, Chivukula V, Gruszka DT, Shan Z, Singh PK, Pye VE, McLean RK, Bedwell GJ, Li W, Nans A, Cook NJ, Fadel HJ, Poeschla EM, Griffiths DJ, Vargas J, Taylor IA, Lyumkis D, Yardimci H, Engelman AN, Cherepanov Pet al., 2022, Multivalent interactions essential for lentiviral integrase function, NATURE COMMUNICATIONS, Vol: 13

Journal article

Rosadas C, Khan M, Parker E, Marchesin F, Katsanovskaja K, Sureda-Vives M, Fernandez N, Randell P, Harvey R, Lilley A, Harris BH, Zuhair M, Fertleman M, Ijaz S, Dicks S, Short C-E, Quinlan R, Taylor GP, Hu K, McKay P, Rosa A, Roustan C, Zuckerman M, El Bouzidi K, Cooke G, Flower B, Moshe M, Elliott P, Spencer AJ, Lambe T, Gilbert SC, Kingston H, Baillie JK, Openshaw PJ, G Semple M, ISARIC4C Investigators, Cherepanov P, O McClure M, S Tedder Ret al., 2022, Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility, Journal of Virological Methods, Vol: 302, ISSN: 0166-0934

Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD). This class and species neutral assay showed a specificity of 100% on 825 pre COVID-19 samples and a potential sensitivity of 99.6% on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralisation and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations. The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.

Journal article

Maertens GN, Engelman AN, Cherepanov P, 2022, Structure and function of retroviral integrase, Nature Reviews Microbiology, Vol: 20, Pages: 20-34, ISSN: 1740-1526

A hallmark of retroviral replication is establishment of the proviral state, wherein a DNA copy of the viral RNA genome is stably incorporated into a host cell chromosome. Integrase is the viral enzyme responsible for the catalytic steps involved in this process, and integrase strand transfer inhibitors are widely used to treat people living with HIV. Over the past decade, a series of X-ray crystallography and cryogenic electron microscopy studies have revealed the structural basis of retroviral DNA integration. A variable number of integrase molecules congregate on viral DNA ends to assemble a conserved intasome core machine that facilitates integration. The structures additionally informed on the modes of integrase inhibitor action and the means by which HIV acquires drug resistance. Recent years have witnessed the development of allosteric integrase inhibitors, a highly promising class of small molecules that antagonize viral morphogenesis. In this Review, we explore recent insights into the organization and mechanism of the retroviral integration machinery and highlight open questions as well as new directions in the field.

Journal article

Davis C, Logan N, Tyson G, Orton R, Harvey WT, Perkins JS, Mollett G, Blacow RM, Peacock TP, Barclay WS, Cherepanov P, Palmarini M, Murcia PR, Patel AH, Robertson DL, Haughney J, Thomson EC, Willett BJet al., 2021, Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination, PLOS PATHOGENS, Vol: 17, ISSN: 1553-7366

Journal article

Alrubayyi A, Gea-Mallorqui E, Touizer E, Hameiri-Bowen D, Kopycinski J, Charlton B, Fisher-Pearson N, Muir L, Rosa A, Roustan C, Earl C, Cherepanov P, Pellegrino P, Waters L, Burns F, Kinloch S, Dong T, Dorrell L, Rowland-Jones S, McCoy LE, Peppa Det al., 2021, Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV, NATURE COMMUNICATIONS, Vol: 12

Journal article

Barski MS, Vanzo T, Zhao XZ, Smith SJ, Ballandras-Colas A, Cronin NB, Pye VE, Hughes SH, Burke TR, Cherepanov P, Maertens GNet al., 2021, Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures (vol 12, 4996, 2021), NATURE COMMUNICATIONS, Vol: 12

Journal article

Arulkumaran N, Snow TAC, Kulkarni A, Brealey D, Rickman HM, Rees-Spear C, Spyer MJ, Heaney J, Garr E, Williams B, Cherepanov P, Kassiotis G, Lunn MP, Ambler G, Houlihan C, McCoy LE, Nastouli E, Singer Met al., 2021, Influence of IL-6 levels on patient survival in COVID-19, JOURNAL OF CRITICAL CARE, Vol: 66, Pages: 123-125, ISSN: 0883-9441

Journal article

Deakin CT, Cornish GH, Ng KW, Faulkner N, Bolland W, Hope J, Rosa A, Harvey R, Hussain S, Earl C, Jebson BR, Wilkinson MGLL, Marshall LR, O'Brien K, Rosser EC, Radziszewska A, Peckham H, Patel H, Heaney J, Rickman H, Paraskevopoulou S, Houlihan CF, Spyer MJ, Gamblin SJ, McCauley J, Nastouli E, Levin M, Cherepanov P, Ciurtin C, Wedderburn LR, Kassiotis Get al., 2021, Favorable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases, MED, Vol: 2, Pages: 1093-+, ISSN: 2666-6340

Journal article

Maertens G, Barski MS, Vanzo T, Zhao X, Smith SJ, Ballandras-Colas A, Cronin NB, Pye VE, Hughes SH, Burke TRJ, Cherepanov Pet al., 2021, Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures, Nature Communications, Vol: 12, Pages: 1-10, ISSN: 2041-1723

Between 10 and 20 million people worldwide are infected with the human T-celllymphotropic virus type 1 (HTLV-1). Despite causing life-threateningpathologies there is no therapeutic regimen for this deltaretrovirus. Here, wescreened a library of integrase strand transfer inhibitor (INSTI) candidates builtaround several chemical scaffolds to determine their effectiveness in limitingHTLV-1 infection. Naphthyridines with substituents in position 6 emerged as themost potent compounds against HTLV-1, with XZ450 having highest efficacy invitro. Using single-particle cryo-electron microscopy we visualised XZ450 aswell as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the activesite of the deltaretroviral intasome. The structures reveal subtle differences inthe coordination environment of the Mg2+ ion pair involved in the interactionwith the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1intasome and support their use for pre-exposure prophylaxis and possiblyfuture treatment of HTLV-1 infection.

Journal article

Arulkumaran N, Snow TAC, Kulkarni A, Brealey D, Rickman H, Rees-Spear C, Spyer MJ, Heaney J, Garr E, Williams B, Cherepanov P, Kassiotis G, Lunn M, Houlihan C, McCoy LE, Nastouli E, Singer Met al., 2021, Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort., Crit Care Explor, Vol: 3

OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or sever

Journal article

Arulkumaran N, Snow TAC, Kulkarni A, Brealey D, Rickman HM, Rees-Spear C, Spyer MJ, Heaney J, Garr E, Williams B, Cherepanov P, Kassiotis G, Lunn MP, Houlihan C, McCoy LE, Nastouli E, Singer Met al., 2021, Sex differences in immunological responses to COVID-19: a cross-sectional analysis of a single-centre cohort, BRITISH JOURNAL OF ANAESTHESIA, Vol: 127, Pages: E75-E78, ISSN: 0007-0912

Journal article

Muir L, Jaffer A, Rees-Spear C, Gopalan V, Chang FY, Fernando R, Vaitkute G, Roustan C, Rosa A, Earl C, Rajakaruna GK, Cherepanov P, Salama A, McCoy LE, Motallebzadeh Ret al., 2021, Neutralizing Antibody Responses After SARS-CoV-2 Infection in End-Stage Kidney Disease and Protection Against Reinfection, KIDNEY INTERNATIONAL REPORTS, Vol: 6, Pages: 1799-1809, ISSN: 2468-0249

Journal article

Davis C, Logan N, Tyson G, Orton R, Harvey W, Haughney J, Perkins J, Peacock TP, Barclay WS, Cherepanov P, Palmarini M, Murcia PR, Patel AH, Robertson DL, Thomson EC, Willett BJet al., 2021, Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination

<jats:title>Abstract</jats:title><jats:p>Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines b

Journal article

Graham C, Seow J, Huettner I, Khan H, Kouphou N, Acors S, Winstone H, Pickering S, Galao RP, Dupont L, Lista MJ, Jimenez-Guardeno JM, Laing AG, Wu Y, Joseph M, Muir L, van Gils MJ, Ng WM, Duyvesteyn HME, Zhao Y, Bowden TA, Shankar-Hari M, Rosa A, Cherepanov P, McCoy LE, Hayday AC, Neil SJD, Malim MH, Doores KJet al., 2021, Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant, IMMUNITY, Vol: 54, Pages: 1276-+, ISSN: 1074-7613

Journal article

Hodakova Z, Nans A, Kunzelmann S, Mehmood S, Taylor I, Uhlmann F, Cherepanov P, Singleton MRet al., 2021, Structural characterisation of the Chaetomium thermophilum Chl1 helicase, PLOS ONE, Vol: 16, ISSN: 1932-6203

Journal article

Rosa A, Pye VE, Graham C, Muir L, Seow J, Ng KW, Cook NJ, Rees-Spear C, Parker E, dos Santos MS, Rosadas C, Susana A, Rhys H, Nans A, Masino L, Roustan C, Christodoulou E, Ulferts R, Wrobel AG, Short C-E, Fertleman M, Sanders RW, Heaney J, Spyer M, Kjaer S, Riddell A, Malim MH, Beale R, MacRae J, Taylor GP, Nastouli E, van Gils MJ, Rosenthal PB, Pizzato M, McClure MO, Tedder RS, Kassiotis G, McCoy LE, Doores KJ, Cherepanov Pet al., 2021, SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity, Science Advances, Vol: 7, Pages: 1-14, ISSN: 2375-2548

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo–electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.

Journal article

Rees-Spear C, Muir L, Griffith SA, Heaney J, Aldon Y, Snitselaar JL, Thomas P, Graham C, Seow J, Lee N, Rosa A, Roustan C, Houlihan CF, Sanders RW, Gupta RK, Cherepanov P, Stauss HJ, Nastouli E, Doores KJ, van Gils MJ, McCoy LEet al., 2021, The effect of spike mutations on SARS-CoV-2 neutralization, CELL REPORTS, Vol: 34, ISSN: 2211-1247

Journal article

Alrubayyi A, Gea-Mallorquí E, Touizer E, Hameiri-Bowen D, Kopycinski J, Charlton B, Fisher-Pearson N, Muir L, Rosa A, Roustan C, Earl C, Cherepanov P, Pellegrino P, Waters L, Burns F, Kinloch S, Dong T, Dorrell L, Rowland-Jones S, McCoy LE, Peppa Det al., 2021, Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV., Res Sq

There is an urgent need to understand the nature of immune responses against SARS-CoV-2, to inform risk-mitigation strategies for people living with HIV (PLWH). We show that the majority of PLWH, controlled on ART, mount a functional adaptive immune response to SARS-CoV-2. Humoral and SARS-CoV-2-specific T cell responses are comparable between HIV-positive and negative subjects and persist 5-7 months following predominately mild COVID-19 disease. T cell responses against Spike, Membrane and Nucleocapsid are the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. We further show that the overall magnitude of SARS-CoV-2-specific T cell responses relates to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH, in whom disparate antibody and T cell responses are observed. These findings suggest that inadequate immune reconstitution on ART, could hinder immune responses to SARS-CoV-2 with implications for the individual management and vaccine effectiveness in PLWH.

Journal article

Smith SJ, Zhao XZ, Passos DO, Pye VE, Cherepanov P, Lyumkis D, Burke TR, Hughes SHet al., 2021, HIV-1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants, ACS INFECTIOUS DISEASES, Vol: 7, Pages: 1469-1482, ISSN: 2373-8227

Journal article

El Bouzidi K, Pirani T, Rosadas C, Ijaz S, Pearn M, Chaudhry S, Patel S, Sureda-Vives M, Fernandez N, Khan M, Cherepanov P, McClure MO, Tedder RS, Zuckerman Met al., 2021, Severe Acute Respiratory Syndrome Coronavirus-2 Infections in Critical Care Staff: Beware the Risks Beyond the Bedside, CRITICAL CARE MEDICINE, Vol: 49, Pages: 428-436, ISSN: 0090-3493

Journal article

Alrubayyi A, Gea-Mallorquí E, Touizer E, Hameiri-Bowen D, Kopycinski J, Charlton B, Fisher-Pearson N, Muir L, Rosa A, Roustan C, Earl C, Cherepanov P, Pellegrino P, Waters L, Burns F, Kinloch S, Dong T, Dorrell L, Rowland-Jones S, McCoy LE, Peppa Det al., 2021, Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV., bioRxiv

There is an urgent need to understand the nature of immune responses generated against SARS-CoV-2, to better inform risk-mitigation strategies for people living with HIV (PLWH). Although not all PLWH are considered immunosuppressed, residual cellular immune deficiency and ongoing inflammation could influence COVID-19 disease severity, the evolution and durability of protective memory responses. Here, we performed an integrated analysis, characterizing the nature, breadth and magnitude of SARS-CoV-2-specific immune responses in PLWH, controlled on ART, and HIV negative subjects. Both groups were in the convalescent phase of predominately mild COVID-19 disease. The majority of PLWH mounted SARS-CoV-2 Spike- and Nucleoprotein-specific antibodies with neutralizing activity and SARS-CoV-2-specific T cell responses, as measured by ELISpot, at levels comparable to HIV negative subjects. T cell responses against Spike, Membrane and Nucleocapsid were the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. Notably, the overall magnitude of SARS-CoV-2-specific T cell responses related to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH, in whom disparate antibody and T cell responses were observed. Both humoral and cellular responses to SARS-CoV-2 were detected at 5-7 months post-infection, providing evidence of medium-term durability of responses irrespective of HIV serostatus. Incomplete immune reconstitution on ART and a low CD4:CD8 ratio could, however, hamper the development of immunity to SARS-CoV-2 and serve as a useful tool for risk stratification of PLWH. These findings have implications for the individual management and potential effectiveness of vaccination against SARS-CoV-2 in PLWH. ONE SENTENCE SUMMARY: Adaptive immune responses to SARS-CoV-2 in the setting of HIV infection.

Journal article

Balestrini S, Koepp MJ, Gandhi S, Rickman HM, Shin GY, Houlihan CF, Anders-Cannon J, Silvennoinen K, Xiao F, Zagaglia S, Hudgell K, Ziomek M, Haimes P, Sampson A, Parker A, Cross JH, Pardington R, Nastouli E, Swanton C, Aitken J, Allen Z, Ambler R, Ambrose K, Ashton E, Avola A, Balakrishnan S, Barns-Jenkins C, Barr G, Barrell S, Basu S, Beale R, Beesley C, Bhardwaj N, Bibi S, Bineva-Todd G, Biswas D, Blackman MJ, Bonnet D, Bowker F, Broncel M, Brooks C, Buck MD, Buckton A, Budd T, Burrell A, Busby L, Bussi C, Butterworth S, Byott M, Byrne F, Byrne R, Caidan S, Campbell J, Canton J, Cardoso A, Carter N, Carvalho L, Carzaniga R, Chandler N, Chen Q, Cherepanov P, Churchward L, Clark G, Clayton B, Gigli CC, Collins Z, Cottrell S, Crawford M, Cubitt L, Cullup T, Davies H, Davis P, Davison D, Dearing V, Debaisieux S, Diaz-Romero M, Dibbs A, Diring J, Driscoll PC, D'Avola A, Earl C, Edwards A, Ekin C, Evangelopoulos D, Faraway R, Fearns A, Ferron A, Fidanis E, Fitz D, Fleming J, Frampton D, Frederico B, Gaiba A, Gait A, Gamblin S, Gartner K, Gaul L, Golding HM, Goldman J, Goldstone R, Dominguez BG, Gong H, Grant PR, Greco M, Grobler M, Guedan A, Gutierrez MG, Hackett F, Hall R, Halldorsson S, Harris S, Hashim S, Hatipoglu E, Healy L, Heaney J, Herbst S, Hewitt G, Higgins T, Hindmarsh S, Hirani R, Hope J, Horton E, Hoskins B, Howell M, Howitt L, Hoyle J, Htun MR, Hubank M, Encabo HH, Hughes D, Hughes J, Huseynova A, Hwang M-S, Instrell R, Jackson D, Jamal-Hanjani M, Jenkins L, Jiang M, Johnson M, Jones L, Kanu N, Kassiotis G, Kelly G, Kiely L, Teixeira AKS, Kirk S, Kjaer S, Knuepfer E, Komarov N, Kotzampaltiris P, Kousis K, Krylova T, Kucharska A, Labrum R, Lambe C, Lappin M, Lee S-A, Levett A, Levett L, Levi M, Liu HW, Loughlin S, Lu W-T, MacRae J, Madoo A, Marczak JA, Martensson M, Martinez T, Marzook B, Matthews J, Matz JM, McCall S, McCoy LE, McKay F, McNamara EC, Minutti CM, Mistry G, Molina-Arcas M, Montaner B, Montgomery K, Moore C, Moore D, Moraiti A, Moreira-Teixeiet al., 2021, Clinical outcomes of COVID-19 in long-term care facilities for people with epilepsy, EPILEPSY & BEHAVIOR, Vol: 115, ISSN: 1525-5050

Journal article

Hughes EC, Amat JAR, Haney J, Parr YA, Logan N, Palmateer N, Nickbakhsh S, Ho A, Cherepanov P, Rosa A, McAuley A, Broos A, Herbert I, Arthur U, Szemiel AM, Roustan C, Dickson E, Gunson RN, Viana M, Willett BJ, Murcia PRet al., 2021, Severe Acute Respiratory Syndrome Coronavirus 2 Serosurveillance in a Patient Population Reveals Differences in Virus Exposure and Antibody-Mediated Immunity According to Host Demography and Healthcare Setting, JOURNAL OF INFECTIOUS DISEASES, Vol: 223, Pages: 971-980, ISSN: 0022-1899

Journal article

Graham C, Seow J, Huettner I, Khan H, Kouphou N, Acors S, Winstone H, Pickering S, Pedro Galao R, Jose Lista M, Jimenez-Guardeno JM, Laing AG, Wu Y, Joseph M, Muir L, Ng WM, Duyvesteyn HME, Zhao Y, Bowden TA, Shankar-Hari M, Rosa A, Cherepanov P, McCoy LE, Hayday AC, Neil SJD, Malim MH, Doores KJet al., 2021, Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS-CoV-2 Spike., bioRxiv

The interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, the N-terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike-reactive monoclonal antibodies from SARS-CoV-2 infected individuals. ≈45% showed neutralizing activity of which ≈20% were NTD-specific. None of the S2-specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD-specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD-specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.

Journal article

Rosa A, Pye VE, Graham C, Muir L, Seow J, Ng KW, Cook NJ, Rees-Spear C, Parker E, Dos Santos MS, Rosadas C, Susana A, Rhys H, Nans A, Masino L, Roustan C, Christodoulou E, Ulferts R, Wrobel A, Short C-E, Fertleman M, Sanders RW, Heaney J, Spyer M, Kjær S, Riddell A, Malim MH, Beale R, MacRae JI, Taylor GP, Nastouli E, van Gils MJ, Rosenthal PB, Pizzato M, McClure MO, Tedder RS, Kassiotis G, McCoy LE, Doores KJ, Cherepanov Pet al., 2021, SARS-CoV-2 recruits a haem metabolite to evade antibody immunity., medRxiv

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.

Journal article

Ng KW, Faulkner N, Cornish GH, Rosa A, Harvey R, Hussain S, Ufferts R, Earl C, Wrobel AG, Benton DJ, Roustan C, Bolland W, Thompson R, Agua-Doce A, Hobson P, Heaney J, Rickman H, Paraskevopoulou S, Houlihan CF, Thomson K, Sanchez E, Shin GY, Spyer MJ, Joshi D, O'Reilly N, Walker PA, Kjaer S, Riddell A, Moore C, Jebson BR, Wilkinson M, Marshall LR, Rosser EC, Radziszewska A, Peckham H, Ciurtin C, Wedderburn LR, Beale R, Swanton C, Gandhi S, Stockinger B, McCauley J, Gambill SJ, McCoy LE, Cherepanov P, Nastouli E, Kassiotis Get al., 2020, Preexisting and de novo humoral immunity to SARS-CoV-2 in humans, Science, Vol: 370, Pages: 1339-1343, ISSN: 0036-8075

Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)–reactive antibodies were detectable using a flow cytometry–based method in SARS-CoV-2–uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S–reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2–uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.

Journal article

O'Nions J, Muir L, Zheng J, Rees-Spear C, Rosa A, Roustan C, Earl C, Cherepanov P, Gupta R, Khwaja A, Jolly C, McCoy LEet al., 2020, SARS-CoV-2 antibody responses in patients with acute leukaemia, LEUKEMIA, Vol: 35, Pages: 289-292, ISSN: 0887-6924

Journal article

Barski M, Minnell J, Pye V, Nans A, Hodakova Z, Cherepanov P, Maertens Get al., 2020, Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ, Nature Communications, Vol: 11, ISSN: 2041-1723

Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.

Journal article

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