Imperial College London

ProfessorPaulKellam

Faculty of MedicineDepartment of Infectious Disease

Professor of Virus Genomics
 
 
 
//

Contact

 

p.kellam

 
 
//

Location

 

460Wright Fleming WingSt Mary's Campus

//

Summary

 

Publications

Publication Type
Year
to

343 results found

Foster GM, Ambrose JC, Hue S, Delpech VC, Fearnhill E, Abecasis AB, Brown AJL, Geretti AMet al., 2014, Novel HIV-1 recombinants spreading across multiple risk groups in the United Kingdom: The identification and phylogeography of circulating recombinant form (CRF) 50_A1D, PLoS ONE, Vol: 9, ISSN: 1932-6203

Background: An increase in non-B HIV-1 infections among men who have sex with men (MSM) in the United Kingdom (UK)has created opportunities for novel recombinants to arise and become established. We used molecular mapping tocharacterize the importance of such recombinants to the UK HIV epidemic, in order to gain insights into transmissiondynamics that can inform control strategies.Methods and Results: A total of 55,556 pol (reverse transcriptase and protease) sequences in the UK HIV Drug ResistanceDatabase were analyzed using Subtype Classification Using Evolutionary Algorithms (SCUEAL). Overall 72 patients sharedthe same A1/D recombination breakpoint in pol, comprising predominantly MSM but also heterosexuals and injecting drugusers (IDUs). In six MSM, full-length single genome amplification of plasma HIV-1 RNA was performed in order tocharacterize the A1/D recombinant. Subtypes and recombination breakpoints were identified using sliding window andjumping profile hidden markov model approaches. Global maximum likelihood trees of gag, pol and env genes were drawnusing FastTree version 2.1. Five of the six strains showed the same novel A1/D recombinant (8 breakpoints), which has beenclassified as CRF50_A1D. The sixth strain showed a complex CRF50_A1D/B/U structure. Divergence dates andphylogeographic inferences were determined using Bayesian Evolutionary Analysis using Sampling Trees (BEAST). Thisestimated that CRF50_A1D emerged in the UK around 1992 in MSM, with subsequent transmissions to heterosexuals andIDUs. Analysis of CRF50_A1D/B/U demonstrated that around the year 2000 CRF50_A1D underwent recombination with asubtype B strain.Conclusions: We report the identification of CRF50_A1D, a novel circulating recombinant that emerged in UK MSM around1992, with subsequent onward transmission to heterosexuals and IDUs, and more recent recombination with subtype B.These findings highlight the changing dynamics of HIV transmission in the UK and the converging of the two pr

Journal article

Gurdasani D, Iles L, Dillon DG, Young EH, Olson AD, Naranbhai V, Fidler S, Gkrania-Klotsas E, Post FA, Kellam P, Porter K, Sandhu MSet al., 2014, A systematic review of definitions of extreme phenotypes of HIV control and progression, AIDS, Vol: 28, Pages: 149-162, ISSN: 0269-9370

The study of individuals at opposite ends of the HIV clinical spectrum can provideinvaluable insights into HIV biology. Heterogeneity in criteria used to define theseindividuals can introduce inconsistencies in results from research and make it difficultto identify biological mechanisms underlying these phenotypes. In this systematicreview, we formally quantified the heterogeneity in definitions used for terms referringto extreme phenotypes in the literature, and identified common definitions andcomponents used to describe these phenotypes. We assessed 714 definitions of HIVextreme phenotypes in 501 eligible studies published between 1 January 2000 and15 March 2012, and identified substantial variation among these. This heterogeneity indefinitions may represent important differences in biological endophenotypes andclinical progression profiles of individuals selected by these, suggesting the need forharmonized definitions. In this context, we were able to identify common componentsin existing definitions that may provide a framework for developing consensusdefinitions for these phenotypes in HIV infection.

Journal article

Dunning JW, Merson L, Rohde GGU, Gao Z, Semple MG, Tran D, Gordon A, Olliaro PL, Khoo SH, Bruzzone R, Horby P, Cobb JP, Longuere K, Kellam P, Nichol A, Brett S, Everett D, Walsh TS, Hien T, Yu H, Zambon M, Ruiz-Palacios G, Lang T, Akhvlediani T, Hayden FG, Marshall J, Webb S, Angus DC, Shindo N, van der Werf S, Openshaw PJM, Farrar J, Carson G, Baillie JKet al., 2014, Open source clinical science for emerging infections, The Lancet Infectious Diseases, Vol: 14, Pages: 8-9, ISSN: 1473-3099

Journal article

Kellam P, 2014, The emerging threats from influenza and MERS coronaviruses, International Workshop on Antiviral Drug Resistance - Meeting the Global Challenge, Publisher: INT MEDICAL PRESS LTD, Pages: A11-A11, ISSN: 1359-6535

Conference paper

Cotten M, Watson SJ, Kellam P, Al-Rabeeah AA, Makhdoom HQ, Assiri A, Al-Tawfiq JA, Alhakeem RF, Madani H, AlRabiah FA, Al Hajjar S, Al-Nassir WN, Albarrak A, Flemban H, Balkhy HH, Alsubaie S, Palser AL, Gall A, Bashford-Rogers R, Rambaut A, Zumla AI, Memish ZAet al., 2013, Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study, The Lancet, Vol: 382, Pages: 1993-2002, ISSN: 0140-6736

BackgroundSince June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin.MethodsFull genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85–95%, and four 30–50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done.FindingsThree distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction.InterpretationWe present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed.FundingSaudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre.

Journal article

Smith SE, Gibson MS, Wash RS, Ferrara F, Wright E, Temperton N, Kellam P, Fife Met al., 2013, Chicken interferon-inducible transmembrane protein 3 restricts influenza viruses and lyssaviruses in vitro, Journal of Virology, Vol: 87, Pages: 12957-12966, ISSN: 1098-5514

Interferon-inducible transmembrane protein 3 (IFITM3) is an effector protein of the innate immune system. It confers potent, cell-intrinsic resistance to infection by diverse enveloped viruses both in vitro and in vivo, including influenza viruses, West Nile virus, and dengue virus. IFITM3 prevents cytosolic entry of these viruses by blocking complete virus envelope fusion with cell endosome membranes. Although the IFITM locus, which includes IFITM1, -2, -3, and -5, is present in mammalian species, this locus has not been unambiguously identified or functionally characterized in avian species. Here, we show that the IFITM locus exists in chickens and is syntenic with the IFITM locus in mammals. The chicken IFITM3 protein restricts cell infection by influenza A viruses and lyssaviruses to a similar level as its human orthologue. Furthermore, we show that chicken IFITM3 is functional in chicken cells and that knockdown of constitutive expression in chicken fibroblasts results in enhanced infection by influenza A virus. Chicken IFITM2 and -3 are constitutively expressed in all tissues examined, whereas IFITM1 is only expressed in the bursa of Fabricius, gastrointestinal tract, cecal tonsil, and trachea. Despite being highly divergent at the amino acid level, IFITM3 proteins of birds and mammals can restrict replication of viruses that are able to infect different host species, suggesting IFITM proteins may provide a crucial barrier for zoonotic infections.

Journal article

Audzevich T, Bashford-Rogers R, Frampton D, Kellam P, Gilroy Det al., 2013, B-1 B cells - a novel source of macrophages during homeostasis and inflammation, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 191-191, ISSN: 0019-2805

Conference paper

Everitt AR, Clare S, McDonald JU, Kane L, Harcourt K, Ahras M, Lall A, Hale C, Rodgers A, Young DB, Haque A, Billker O, Tregoning JS, Dougan G, Kellam Pet al., 2013, Defining the Range of Pathogens Susceptible to Ifitm3 Restriction Using a Knockout Mouse Model, PLOS ONE, Vol: 8, ISSN: 1932-6203

Journal article

Munnink BBO, Farsani SMJ, Deijs M, Jonkers J, Verhoeven JTP, Ieven M, Goossens H, de Jong MD, Berkhout B, Loens K, Kellam P, Bakker M, Canuti M, Cotten M, van der Hoek Let al., 2013, Autologous antibody capture to enrich immunogenic viruses for viral discovery, PLoS ONE, Vol: 8, ISSN: 1932-6203

Discovery of new viruses has been boosted by novel deep sequencing technologies. Currently, many viruses can be identified by sequencing without knowledge of the pathogenicity of the virus. However, attributing the presence of a virus in patient material to a disease in the patient can be a challenge. One approach to meet this challenge is identification of viral sequences based on enrichment by autologous patient antibody capture. This method facilitates identification of viruses that have provoked an immune response within the patient and may increase the sensitivity of the current virus discovery techniques. To demonstrate the utility of this method, virus discovery deep sequencing (VIDISCA-454) was performed on clinical samples from 19 patients: 13 with a known respiratory viral infection and 6 with a known gastrointestinal viral infection. Patient sera was collected from one to several months after the acute infection phase. Input and antibody capture material was sequenced and enrichment was assessed. In 18 of the 19 patients, viral reads from immunogenic viruses were enriched by antibody capture (ranging between 1.5x to 343x in respiratory material, and 1.4x to 53x in stool). Enriched reads were also determined in an identity independent manner by using a novel algorithm Xcompare. In 16 of the 19 patients, 21% to 100% of the enriched reads were derived from infecting viruses. In conclusion, the technique provides a novel approach to specifically identify immunogenic viral sequences among the bulk of sequences which are usually encountered during virus discovery metagenomics.

Journal article

Bashford-Rogers RJM, Palser AL, Huntly BJ, Rance R, Vassiliou GS, Follows GA, Kellam Pet al., 2013, Network properties derived from deep sequencing of human B-cell receptor repertoires delineate B-cell populations, Genome Research, Vol: 23, Pages: 1874-1884, ISSN: 1054-9803

The adaptive immune response selectively expands B- and T-cell clones following antigen recognition by B- and T-cell receptors (BCR and TCR), respectively. Next-generation sequencing is a powerful tool for dissecting the BCR and TCR populations at high resolution, but robust computational analyses are required to interpret such sequencing. Here, we develop a novel computational approach for BCR repertoire analysis using established next-generation sequencing methods coupled with network construction and population analysis. BCR sequences organize into networks based on sequence diversity, with differences in network connectivity clearly distinguishing between diverse repertoires of healthy individuals and clonally expanded repertoires from individuals with chronic lymphocytic leukemia (CLL) and other clonal blood disorders. Network population measures defined by the Gini Index and cluster sizes quantify the BCR clonality status and are robust to sampling and sequencing depths. BCR network analysis therefore allows the direct and quantifiable comparison of BCR repertoires between samples and intra-individual population changes between temporal or spatially separated samples and over the course of therapy.

Journal article

Lin T-Y, Chin CR, Everitt AR, Clare S, Perreira JM, Savidis G, Aker AM, John SP, Sarlah D, Carreira EM, Elledge SJ, Kellam P, Brass ALet al., 2013, Amphotericin B increases influenza A virus infection by preventing IFITM3-mediated restriction, Cell Reports, Vol: 5, Pages: 895-908, ISSN: 2211-1247

The IFITMs inhibit influenza A virus (IAV) replication in vitro and in vivo. Here, we establish that the antimycotic heptaen, amphotericin B (AmphoB), prevents IFITM3-mediated restriction of IAV, thereby increasing viral replication. Consistent with its neutralization of IFITM3, a clinical preparation of AmphoB, AmBisome, reduces the majority of interferon’s protective effect against IAV in vitro. Mechanistic studies reveal that IFITM1 decreases host-membrane fluidity, suggesting both a possible mechanism for IFITM-mediated restriction and its negation by AmphoB. Notably, we reveal that mice treated with AmBisome succumbed to a normally mild IAV infection, similar to animals deficient in Ifitm3. Therefore, patients receiving antifungal therapy with clinical preparations of AmphoB may be functionally immunocompromised and thus more vulnerable to influenza, as well as other IFITM3-restricted viral infections.

Journal article

Castro H, Pillay D, Cane P, Asboe D, Cambiano V, Phillips A, Dunn DTet al., 2013, Persistence of HIV-1 transmitted drug resistance mutations, Journal of Infectious Diseases, Vol: 208, Pages: 1459-1463, ISSN: 0022-1899

There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.

Journal article

Dolling DI, Dunn DT, Sutherland KA, Pillay D, Mbisa JL, Parry CM, Post FA, Sabin CA, Cane PAet al., 2013, Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study, Journal of Antimicrobial Chemotherapy, Vol: 68, Pages: 2339-2343, ISSN: 0305-7453

ObjectivesTo determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.MethodsResistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.ResultsFour hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84–3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (Pā€Š<ā€Š0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (Pā€Š<ā€Š0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.ConclusionsViral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.

Journal article

Mackie NE, Dunn DT, Dolling D, Garvey L, Harrison L, Fearnhill E, Tilston P, Sabin C, Geretti AMet al., 2013, The impact of HIV-1 reverse transcriptase polymorphisms on responses to first-line nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-1-infected adults, AIDS, Vol: 27, Pages: 2245-2253, ISSN: 0269-9370

Journal article

Alkhamis M, Perez A, Batey N, Howard W, Baillie G, Watson S, Franz S, Focosi-Snyman R, Onita I, Cioranu R, Turcitu M, Kellam P, Brown IH, Breed ACet al., 2013, Modeling the Association of Space, Time, and Host Species with Variation of the HA, NA, and NS Genes of H5N1 Highly Pathogenic Avian Influenza Viruses Isolated from Birds in Romania in 2005-2007, AVIAN DISEASES, Vol: 57, Pages: 612-621, ISSN: 0005-2086

Journal article

Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, Cummings DAT, Alabdullatif ZN, Assad M, Almulhim A, Makhdoom H, Madani H, Alhakeem R, Al-Tawfiq JA, Cotten M, Watson SJ, Kellam P, Zumla AI, Memish ZAet al., 2013, Hospital Outbreak of Middle East Respiratory Syndrome Coronavirus, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 369, Pages: 407-416, ISSN: 0028-4793

Journal article

Baker KS, Leggett RM, Bexfield NH, Alston M, Daly G, Todd S, Tachedjian M, Holmes CEG, Crameri S, Wang L-F, Heeney JL, Suu-Ire R, Kellam P, Cunningham AA, Wood JLN, Caccamo M, Murcia PRet al., 2013, Metagenomic study of the viruses of African straw-coloured fruit bats: Detection of a chiropteran poxvirus and isolation of a novel adenovirus, Virology, Vol: 441, Pages: 95-106, ISSN: 0042-6822

Viral emergence as a result of zoonotic transmission constitutes a continuous public health threat. Emerging viruses such as SARS coronavirus, hantaviruses and henipaviruses have wildlife reservoirs. Characterising the viruses of candidate reservoir species in geographical hot spots for viral emergence is a sensible approach to develop tools to predict, prevent, or contain emergence events. Here, we explore the viruses of Eidolon helvum, an Old World fruit bat species widely distributed in Africa that lives in close proximity to humans. We identified a great abundance and diversity of novel herpes and papillomaviruses, described the isolation of a novel adenovirus, and detected, for the first time, sequences of a chiropteran poxvirus closely related with Molluscum contagiosum. In sum, E. helvum display a wide variety of mammalian viruses, some of them genetically similar to known human pathogens, highlighting the possibility of zoonotic transmission.

Journal article

Kati S, Tsao EH, Guenther T, Weidner-Glunde M, Rothaemel T, Grundhoff A, Kellam P, Schulz TFet al., 2013, Activation of the B Cell Antigen Receptor Triggers Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus in B Cells, JOURNAL OF VIROLOGY, Vol: 87, Pages: 8004-8016, ISSN: 0022-538X

Journal article

John SP, Chin CR, Perreira JM, Feeley EM, Aker AM, Savidis G, Smith SE, Elia AEH, Everitt AR, Vora M, Pertel T, Elledge SJ, Kellam P, Brass ALet al., 2013, The CD225 Domain of IFITM3 Is Required for both IFITM Protein Association and Inhibition of Influenza A Virus and Dengue Virus Replication, JOURNAL OF VIROLOGY, Vol: 87, Pages: 7837-7852, ISSN: 0022-538X

Journal article

Gagnier JJ, Kellam PJ, 2013, Reporting and methodological quality of systematic reviews in the orthopaedic literature., J Bone Joint Surg Am, Vol: 95, Pages: e771-e777

BACKGROUND: Properly designed and conducted systematic reviews can reliably produce valid pooled treatment-effect estimates and are an important resource for clinical decision-making. The purpose of this report was to assess the reporting and methodological quality of systematic reviews in orthopaedic journals. METHODS: With use of the 2010 Institute for Scientific Information (ISI) Thomson Reuters Journal Citation Reports, the five orthopaedic surgery journals with the highest impact factors were searched by one individual over a five-year period (from 2006 to 2010) for systematic reviews and meta-analyses. The two authors separately and independently assessed the included studies. The reporting quality was assessed with use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the methodological quality was assessed with use of the Assessment of Multiple Systematic Reviews (AMSTAR) guidelines, both of which are accepted instruments. We calculated the proportions of each item reported within and across journals. RESULTS: Seventy-six systematic reviews and meta-analyses were included. Of the five journals that were examined, articles from The Journal of Bone and Joint Surgery (American Volume) had the best reporting. Articles from The American Journal of Sports Medicine fulfilled the most methodological quality items. The papers from all of the journals reported an average of only 68% of the PRISMA items and only 54% of the AMSTAR quality items. CONCLUSIONS: Both reporting and methodological quality in the top five orthopaedic journals were poor; the reporting quality was slightly superior to the methodological quality. Although there was a wide range of reporting quality and methodological quality scores across the journals, the included articles demonstrated inadequate adherence to accepted standards of quality. The use of PRISMA and AMSTAR guidelines in designing, implementing, and writing systematic reviews is recommen

Journal article

Koning FA, Castro H, Dunn D, Tilston P, Cane PA, Mbisa JLet al., 2013, Subtype-specific differences in the development of accessory mutations associated with high-level resistance to HIV-1 nucleoside reverse transcriptase inhibitors, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 68, Pages: 1220-1236, ISSN: 0305-7453

Journal article

Cotten M, Lam TT, Watson SJ, Palser AL, Petrova V, Grant P, Pybus OG, Rambaut A, Guan Y, Pillay D, Kellam P, Nastouli Eet al., 2013, Full-genome deep sequencing and phylogenetic analysis of novel human betacoronavirus., Emerging Infectious Diseases, Vol: 19, Pages: 736-742B, ISSN: 1080-6040

A novel betacoronavirus associated with lethal respiratory and renal complications was recently identified in patients from several countries in the Middle East. We report the deep genome sequencing of the virus directly from a patient's sputum sample. Our high-throughput sequencing yielded a substantial depth of genome sequence assembly and showed the minority viral variants in the specimen. Detailed phylogenetic analysis of the virus genome (England/Qatar/2012) revealed its close relationship to European bat coronaviruses circulating among the bat species of the Vespertilionidae family. Molecular clock analysis showed that the 2 human infections of this betacoronavirus in June 2012 (EMC/2012) and September 2012 (England/Qatar/2012) share a common virus ancestor most likely considerably before early 2012, suggesting the human diversity is the result of multiple zoonotic events.

Journal article

De Luca A, Dunn D, Zazzi M, Camacho R, Torti C, Fanti I, Kaiser R, Sonnerborg A, Codoner FM, Van Laethem K, Vandamme A-M, Bansi L, Ghisetti V, van de Vijver DAMC, Asboe D, Prosperi MCF, Di Giambenedetto Set al., 2013, Declining Prevalence of HIV-1 Drug Resistance in Antiretroviral Treatment-exposed Individuals in Western Europe, JOURNAL OF INFECTIOUS DISEASES, Vol: 207, Pages: 1216-1220, ISSN: 0022-1899

Journal article

Murcia PR, Baillie GJ, Stack JC, Jervis C, Elton D, Mumford JA, Daly J, Kellam P, Grenfell BT, Holmes EC, Wood JLNet al., 2013, Evolution of Equine Influenza Virus in Vaccinated Horses, JOURNAL OF VIROLOGY, Vol: 87, Pages: 4768-4771, ISSN: 0022-538X

Journal article

Bhatt S, Lam TT, Lycett SJ, Brown AJL, Bowden TA, Holmes EC, Guan Y, Wood JLN, Brown IH, Kellam P, Pybus OGet al., 2013, The evolutionary dynamics of influenza A virus adaptation to mammalian hosts, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 368, ISSN: 0962-8436

Journal article

Watson SJ, Welkers MRA, Depledge DP, Coulter E, Breuer JM, de Jong MD, Kellam Pet al., 2013, Viral population analysis and minority-variant detection using short read next-generation sequencing, Philosophical Transactions of the Royal Society of London: Biological Sciences, Vol: 368, ISSN: 0962-8436

RNA viruses within infected individuals exist as a population of evolutionary-related variants. Owing to evolutionary change affecting the constitution of this population, the frequency and/or occurrence of individual viral variants can show marked or subtle fluctuations. Since the development of massively parallel sequencing platforms, such viral populations can now be investigated to unprecedented resolution. A critical problem with such analyses is the presence of sequencing-related errors that obscure the identification of true biological variants present at low frequency. Here, we report the development and assessment of the Quality Assessment of Short Read (QUASR) Pipeline (http://sourceforge.net/projects/quasr) specific for virus genome short read analysis that minimizes sequencing errors from multiple deep-sequencing platforms, and enables post-mapping analysis of the minority variants within the viral population. QUASR significantly reduces the error-related noise in deep-sequencing datasets, resulting in increased mapping accuracy and reduction of erroneous mutations. Using QUASR, we have determined influenza virus genome dynamics in sequential samples from an in vitro evolution of 2009 pandemic H1N1 (A/H1N1/09) influenza from samples sequenced on both the Roche 454 GSFLX and Illumina GAIIx platforms. Importantly, concordance between the 454 and Illumina sequencing allowed unambiguous minority-variant detection and accurate determination of virus population turnover in vitro.

Journal article

Kelly GL, Stylianou J, Rasaiyaah J, Wei W, Thomas W, Croom-Carter D, Kohler C, Spang R, Woodman C, Kellam P, Rickinson AB, Bell AIet al., 2013, Different Patterns of Epstein-Barr Virus Latency in Endemic Burkitt Lymphoma (BL) Lead to Distinct Variants within the BL-Associated Gene Expression Signature, JOURNAL OF VIROLOGY, Vol: 87, Pages: 2882-2894, ISSN: 0022-538X

Journal article

Zhang Y-H, Zhao Y, Li N, Peng Y-C, Giannoulatou E, Jin R-H, Yan H-P, Wu H, Liu J-H, Liu N, Wang D-Y, Shu Y-L, Ho L-P, Kellam P, McMichael A, Dong Tet al., 2013, Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals., Nature Communications, Vol: 4, ISSN: 2041-1723

The SNP rs12252-C allele alters the function of interferon-induced transmembrane protein-3 increasing the disease severity of influenza virus infection in Caucasians, but the allele is rare. However, rs12252-C is much more common in Han Chinese. Here we report that the CC genotype is found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. Specifically, the CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. More importantly, because the risk genotype occurs with such a high frequency, its effect translates to a large population-attributable risk of 54.3% for severe infection in the Chinese population studied compared with 5.4% in Northern Europeans. Interferon-induced transmembrane protein-3 genetic variants could, therefore, have a strong effect of the epidemiology of influenza in China and in people of Chinese descent.

Journal article

Gall A, Kaye S, Hue S, Bonsall D, Rance R, Baillie GJ, Fidler SJ, Weber JN, McClure MO, Kellam Pet al., 2013, Restriction of V3 region sequence divergence in the HIV-1 envelope gene during antiretroviral treatment in a cohort of recent seroconverters, Retrovirology, Vol: 10, ISSN: 1742-4690

Background: Dynamic changes in Human Immunodeficiency Virus 1 (HIV-1) sequence diversity and divergence areassociated with immune control during primary infection and progression to AIDS. Consensus sequencing or singlegenome amplification sequencing of the HIV-1 envelope (env) gene, in particular the variable (V) regions, is used asa marker for HIV-1 genome diversity, but population diversity is only minimally, or semi-quantitatively sampledusing these methods.Results: Here we use second generation deep sequencing to determine inter-and intra-patient sequenceheterogeneity and to quantify minor variants in a cohort of individuals either receiving or not receivingantiretroviral treatment following seroconversion; the SPARTAC trial. We show, through a cross-sectional study ofsequence diversity of the env V3 in 30 antiretroviral-naive patients during primary infection that considerablepopulation structure diversity exists, with some individuals exhibiting highly constrained plasma virus diversity.Diversity was independent of clinical markers (viral load, time from seroconversion, CD4 cell count) of infection.Serial sampling over 60 weeks of non-treated individuals that define three initially different diversity profiles showedthat complex patterns of continuing HIV-1 sequence diversification and divergence could be readily detected.Evidence for minor sequence turnover, emergence of new variants and re-emergence of archived variants could beinferred from this analysis. Analysis of viral divergence over the same time period in patients who received short(12 weeks, ART12) or long course antiretroviral therapy (48 weeks, ART48) and a non-treated control group revealedthat ART48 successfully suppressed viral divergence while ART12 did not have a significant effect.Conclusions: Deep sequencing is a sensitive and reliable method for investigating the diversity of the env V3 as animportant component of HIV-1 genome diversity. Detailed insights into the complex early intra-patie

Journal article

Gall A, Ferns B, Morris C, Watson S, Cotten M, Robinson M, Berry N, Pillay D, Kellam Pet al., 2012, Universal Amplification, Next-Generation Sequencing, and Assembly of HIV-1 Genomes, JOURNAL OF CLINICAL MICROBIOLOGY, Vol: 50, Pages: 3838-3844, ISSN: 0095-1137

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: limit=30&id=00599638&person=true&page=7&respub-action=search.html