Imperial College London

ProfessorGeorgiosKassiotis

Faculty of MedicineDepartment of Infectious Disease

Professor of Retrovirology
 
 
 
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Contact

 

g.kassiotis Website

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

89 results found

Au L, Fendler A, Shepherd STC, Rzeniewicz K, Cerrone M, Byrne F, Carlyle E, Edmonds K, Del Rosario L, Shon J, Haynes WA, Ward B, Shum B, Gordon W, Gerard CL, Xie W, Joharatnam-Hogan N, Young K, Pickering L, Furness AJS, Larkin J, Harvey R, Kassiotis G, Gandhi S, Swanton C, Fribbens C, Wilkinson KA, Wilkinson RJ, Lau DK, Banerjee S, Starling N, Chau I, Turajlic Set al., 2021, Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2, Nature Medicine, Vol: 27, Pages: 1362-1366, ISSN: 1078-8956

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population.

Journal article

Faulkner N, Ng KW, Wu MY, Harvey R, Margaritis M, Paraskevopoulou S, Houlihan C, Hussain S, Greco M, Bolland W, Warchal S, Heaney J, Rickman H, Spyer M, Frampton D, Byott M, de Oliveira T, Sigal A, Kjaer S, Swanton C, Gandhi S, Beale R, Gamblin SJ, McCauley JW, Daniels RS, Howell M, Bauer D, Nastouli E, Kassiotis Get al., 2021, Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains, ELIFE, Vol: 10, ISSN: 2050-084X

Journal article

Ottina E, Panova V, Doglio L, Kazachenka A, Cornish G, Kirkpatrick J, Attig J, Young GR, Litchfield K, Lesluyes T, Van Loo P, Swanton C, MacRae J, Tuting T, Kassiotis Get al., 2021, E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion, ONCOGENE, ISSN: 0950-9232

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, ISSN: 2375-2548

Journal article

Buck MD, Poirier EZ, Cardoso A, Frederico B, Canton J, Barrell S, Beale R, Byrne R, Caidan S, Crawford M, Cubitt L, Gandhi S, Goldstone R, Grant PR, Gulati K, Hindmarsh S, Howell M, Hubank M, Instrell R, Jiang M, Kassiotis G, Lu W-T, MacRae JI, Martini I, Miller D, Moore D, Nastouli E, Nicod J, Nightingale L, Olsen J, Oomatia A, O'Reilly N, Rideg A, Song O-R, Strange A, Swanton C, Turajlic S, Wu M, Reis e Sousa Cet al., 2021, SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay, Wellcome Open Research, Vol: 6, Pages: 9-9

<ns4:p>The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARS-CoV-2 detection by RT-LAMP in 25 minutes that is robust, reliable, repeatable, sensitive, specific, and inexpensive.</ns4:p>

Journal article

Buck MD, Poirier EZ, Cardoso A, Frederico B, Canton J, Barrell S, Beale R, Byrne R, Caidan S, Crawford M, Cubitt L, Gandhi S, Goldstone R, Grant PR, Gulati K, Hindmarsh S, Howell M, Hubank M, Instrell R, Jiang M, Kassiotis G, Lu W-T, MacRae JI, Martini I, Miller D, Moore D, Nastouli E, Nicod J, Nightingale L, Olsen J, Oomatia A, O'Reilly N, Rideg A, Song O-R, Strange A, Swanton C, Turajlic S, Wu M, Reis E Sousa C, Crick COVID-19 Consortiumet al., 2021, SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay., Wellcome Open Res, Vol: 6, ISSN: 2398-502X

The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARS-CoV-2 detection by RT-LAMP that is robust, reliable, repeatable, specific, and inexpensive.

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

Ng KW, Attig J, Bolland W, Young GR, Major J, Wrobel AG, Gamblin S, Wack A, Kassiotis Get al., 2020, Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option, NATURE GENETICS, Vol: 52, Pages: 1294-1302, ISSN: 1061-4036

Journal article

Houlihan CF, Vora N, Byrne T, Lewer D, Kelly G, Heaney J, Gandhi S, Spyer MJ, Beale R, Cherepanov P, Moore D, Gilson R, Gamblin S, Kassiotis G, McCoy LE, Swanton C, Hayward A, Nastouli Eet al., 2020, Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers, LANCET, Vol: 396, Pages: E6-E7, ISSN: 0140-6736

Journal article

Aitken J, Ambrose K, Barrell S, Beale R, Bineva-Todd G, Biswas D, Byrne R, Caidan S, Cherepanov P, Churchward L, Clark G, Crawford M, Cubitt L, Dearing V, Earl C, Edwards A, Ekin C, Fidanis E, Gaiba A, Gamblin S, Gandhi S, Goldman J, Goldstone R, Grant PR, Greco M, Heaney J, Hindmarsh S, Houlihan CF, Howell M, Hubank M, Hughes D, Instrell R, Jackson D, Jamal-Hanjani M, Jiang M, Johnson M, Jones L, Kanu N, Kassiotis G, Kirk S, Kjaer S, Levett A, Levett L, Levi M, Lu W-T, MacRae JI, Matthews J, Mccoy LE, Moore C, Moore D, Nastouli E, Nicod J, Nightingale L, Olsen J, O'Reilly N, Pabari A, Papayannopoulos V, Patel N, Peat N, Pollitt M, Ratcliffe P, Reis e Sousa C, Rosa A, Rosenthal R, Roustan C, Rowan A, Shin GY, Snell DM, Song O-R, Spyer MJ, Strange A, Swanton C, Turner JMA, Turner M, Wack A, Walker PA, Ward S, Wong WK, Wright J, Wu Met al., 2020, Scalable and robust SARS-CoV-2 testing in an academic center (vol 47, pg 613, 2020), NATURE BIOTECHNOLOGY, Vol: 38, Pages: 1000-1000, ISSN: 1087-0156

Journal article

Toboso-Navasa A, Gunawan A, Morlino G, Nakagawa R, Taddei A, Damry D, Patel Y, Chakravarty P, Janz M, Kassiotis G, Brink R, Eilers M, Calado DPet al., 2020, Restriction of memory B cell differentiation at the germinal center B cell positive selection stage., J Exp Med, Vol: 217

Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.

Journal article

Aitken J, Ambrose K, Barrell S, Beale R, Bineva-Todd G, Biswas D, Byrne R, Caidan S, Cherepanov P, Churchward L, Clark G, Crawford M, Cubitt L, Dearing V, Earl C, Edwards A, Ekin C, Fidanis E, Gaiba A, Gamblin S, Gandhi S, Goldman J, Goldstone R, Grant PR, Greco M, Heaney J, Hindmarsh S, Houlihan CF, Howell M, Hubank M, Hughes D, Instrell R, Jackson D, Jamal-Hanjani M, Jiang M, Johnson M, Jones L, Kanu N, Kassiotis G, Kirk S, Kjaer S, Levett A, Levett L, Levi M, Lu W-T, MacRae JI, Matthews J, McCoy LE, Moore C, Moore D, Nastouli E, Nicod J, Nightingale L, Olsen J, O'Reilly N, Pabari A, Papayannopoulos V, Patel N, Peat N, Pollitt M, Ratcliffe P, Sousa C, Rosa A, Rosenthal R, Roustan C, Rowan A, Shin GY, Snell DM, Song O-R, Spyer MJ, Strange A, Swanton C, Turner JMA, Turner M, Wack A, Walker PA, Ward S, Wong WK, Wright J, Wu Met al., 2020, Scalable and robust SARS-CoV-2 testing in an academic center, Nature Biotechnology, Vol: 38, Pages: 927-931, ISSN: 1087-0156

Journal article

Panova V, Attig J, Young GR, Stoye JP, Kassiotis Get al., 2020, Antibody-induced internalisation of retroviral envelope glycoproteins is a signal initiation event, PLOS PATHOGENS, Vol: 16, ISSN: 1553-7366

Journal article

Danelli L, Cornish G, Merkenschlager J, Kassiotis Get al., 2020, Default polyfunctional T helper 1 response to ample signal 1 alone, CELLULAR & MOLECULAR IMMUNOLOGY, Vol: 18, Pages: 1809-1822, ISSN: 1672-7681

Journal article

Jiao H, Wachsmuth L, Kumari S, Schwarzer R, Lin J, Eren RO, Fisher A, Lane R, Young GR, Kassiotis G, Kaiser WJ, Pasparakis M, Jiao H, Wachsmuth L, Kumari S, Schwarzer R, Lin J, Eren RO, Fisher A, Lane R, Young GR, Kassiotis G, Kaiser WJ, Pasparakis Met al., 2020, Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation, NATURE, Vol: 580, Pages: 391-+, ISSN: 0028-0836

Journal article

Sledzinska A, de Mucha MV, Bergerhoff K, Hotblack A, Demane DF, Ghorani E, Akarca AU, Marzolini MA, Solomon I, Vargas FA, Pule M, Ono M, Seddon B, Kassiotis G, Ariyan CE, Kom T, Marafioti T, Lord GM, Stauss H, Jenner RG, Peggs KS, Quezada SAet al., 2020, Regulatory T Cells Restrain Interleukin-2-and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4(+) T Cells, IMMUNITY, Vol: 52, Pages: 151-+, ISSN: 1074-7613

Journal article

Kazachenka A, Young GR, Attig J, Kordella C, Lamprianidou E, Zoulia E, Vrachiolias G, Papoutselis M, Bernard E, Papaemmanuil E, Kotsianidis I, Kassiotis Get al., 2019, Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression, GENOME MEDICINE, Vol: 11, ISSN: 1756-994X

Journal article

Ng KW, Attig J, Young GR, Ottina E, Papamichos SI, Kotsianidis I, Kassiotis Get al., 2019, Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist, ELIFE, Vol: 8, ISSN: 2050-084X

Journal article

Attig J, Young GR, Hosie L, Perkins D, Encheva-Yokoya V, Stoye JP, Snijders AP, Ternette N, Kassiotis Get al., 2019, LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly, Genome Research, Vol: 29, Pages: 1578-1590, ISSN: 1054-9803

Dysregulated endogenous retroelements (EREs) are increasingly implicated in the initiation, progression, and immune surveillance of human cancer. However, incomplete knowledge of ERE activity limits mechanistic studies. By using pan-cancer de novo transcript assembly, we uncover the extent and complexity of ERE transcription. The current assembly doubled the number of previously annotated transcripts overlapping with long-terminal repeat (LTR) elements, several thousand of which were expressed specifically in one or a few related cancer types. Exemplified in melanoma, LTR-overlapping transcripts were highly predictable, disease prognostic, and closely linked with molecularly defined subtypes. They further showed the potential to affect disease-relevant genes, as well as produce novel cancer-specific antigenic peptides. This extended view of LTR elements provides the framework for functional validation of affected genes and targets for cancer immunotherapy.

Journal article

Dittmer U, Sutter K, Kassiotis G, Zelinskyy G, Bánki Z, Stoiber H, Santiago ML, Hasenkrug KJet al., 2019, Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity, FEMS Microbiology Reviews, Vol: 43, Pages: 435-456, ISSN: 0168-6445

Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type 1 interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feed-back mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.

Journal article

Merkenschlager J, Eksmond U, Danelli L, Attig J, Young GR, Nowosad C, Tolar P, Kassiotis Get al., 2019, MHC class II cell-autonomously regulates self-renewal and differentiation of normal and malignant B cells, Blood, Vol: 133, Pages: 1108-1118, ISSN: 1528-0020

Best known for presenting antigenic peptides to CD4+ T cells, major histocompatibility complex class II (MHC II) also transmits or may modify intracellular signals. Here, we show that MHC II cell-autonomously regulates the balance between self-renewal and differentiation in B-cell precursors, as well as in malignant B cells. Initiation of MHC II expression early during bone marrow B-cell development limited the occupancy of cycling compartments by promoting differentiation, thus regulating the numerical output of B cells. MHC II deficiency preserved stem cell characteristics in developing pro-B cells in vivo, and ectopic MHC II expression accelerated hematopoietic stem cell differentiation in vitro. Moreover, MHC II expression restrained growth of murine B-cell leukemia cell lines in vitro and in vivo, independently of CD4+ T-cell surveillance. Our results highlight an important cell-intrinsic contribution of MHC II expression to establishing the differentiated B-cell phenotype.

Journal article

Uchil PD, Pi R, Haugh KA, Ladinsky MS, Ventura JD, Barrett BS, Santiago ML, Bjorkman PJ, Kassiotis G, Sewald X, Mothes Wet al., 2019, A protective role for the Lectin CD169/Siglec-1 against a pathogenic murine retrovirus, Cell Host and Microbe, Vol: 25, Pages: 87-100.e10, ISSN: 1931-3128

Lymph- and blood-borne retroviruses exploit CD169/Siglec-1-mediated capture by subcapsular sinus and marginal zone metallophilic macrophages for trans-infection of permissive lymphocytes. However, the impact of CD169-mediated virus capture on retrovirus dissemination and pathogenesis in vivo is unknown. In a murine model of the splenomegaly-inducing retrovirus Friend virus complex (FVC) infection, we find that while CD169 promoted draining lymph node infection, it limited systemic spread to the spleen. At the spleen, CD169-expressing macrophages captured incoming blood-borne retroviruses and limited their spread to the erythroblasts in the red pulp where FVC manifests its pathogenesis. CD169-mediated retroviral capture activated conventional dendritic cells 1 (cDC1s) and promoted cytotoxic CD8+ T cell responses, resulting in efficient clearing of FVC-infected cells. Accordingly, CD169 blockade led to higher viral loads and accelerated death in susceptible mouse strains. Thus, CD169 plays a protective role during FVC pathogenesis by reducing viral dissemination to erythroblasts and eliciting an effective cytotoxic T lymphocyte response via cDC1s.

Journal article

Kordella C, Kazachenka A, Lamprianidou E, Zoulia E, Vrachiolias G, Papoutselis MK, Bezirgiannidou Z, Spanoudakis E, Georgiou C, Eksmond U, Kassiotis G, Kotsianidis Iet al., 2018, The Therapeutic Response of Myelodsyplastic Syndromes to Azacytidine Is Independent of Endogenous Retroelement Modulation, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Ottina E, Levy P, Eksmond U, Merkenschlager J, Young GR, Roels J, Stoye JP, Tueting T, Calado DP, Kassiotis Get al., 2018, Restoration of Endogenous Retrovirus Infectivity Impacts Mouse Cancer Models, CANCER IMMUNOLOGY RESEARCH, Vol: 6, Pages: 1292-1300, ISSN: 2326-6066

Journal article

Danelli L, Donnarumma T, Kassiotis G, 2018, Correlates of follicular helper bias in the CD4 T cell response to a retroviral antigen, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224

CD4+ T cell differentiation is influenced by a plethora of intrinsic and extrinsic factors, providing the immune system with the ability to tailor its response according to specific stimuli. Indeed, different classes of pathogens may induce a distinct balance of CD4+ T cell differentiation programmes. Here, we report an uncommonly strong bias toward follicular helper (Tfh) differentiation of CD4+ T cells reactive with a retroviral envelope glycoprotein model antigen, presented in its natural context during retroviral infection. Conversely, the response to the same antigen, presented in different immunization regimens, elicited a response typically balanced between Tfh and T helper 1 cells. Comprehensive quantitation of variables known to influence Tfh differentiation revealed the closest correlation with the strength of T cell receptor (TCR) signaling, leading to PD-1 expression, but not with surface TCR downregulation, irrespective of TCR clonotypic avidity. In contrast, strong TCR signaling leading to TCR downregulation and induction of LAG3 expression in high TCR avidity clonotypes restrained CD4+ T cell commitment and further differentiation. Finally, stunted Th1 differentiation, correlating with limited IL-2 availability in retroviral infection, provided permissive conditions for Tfh development, suggesting that Tfh differentiation is the default program of envelope-reactive CD4+ T cells.

Journal article

Fontaine M, Vogel I, Van Eycke Y-R, Galuppo A, Ajouaou Y, Decaestecker C, Kassiotis G, Moser M, Leo Oet al., 2018, Regulatory T cells constrain the TCR repertoire of antigen-stimulated conventional CD4 T cells, EMBO JOURNAL, Vol: 37, Pages: 398-412, ISSN: 0261-4189

Journal article

Attig J, Young GR, Stoye JP, Kassiotis Get al., 2017, Physiological and pathological transcriptional activation of endogenous retroelements assessed by RNA-sequencing of B lymphocytes, Frontiers in Microbiology, Vol: 8, ISSN: 1664-302X

In addition to evolutionarily-accrued sequence mutation or deletion, endogenous retroelements (EREs) in eukaryotic genomes are subject to epigenetic silencing, preventing or reducing their transcription, particularly in the germplasm. Nevertheless, transcriptional activation of EREs, including endogenous retroviruses (ERVs) and long interspersed nuclear elements (LINEs), is observed in somatic cells, variably upon cellular differentiation and frequently upon cellular transformation. ERE transcription is modulated during physiological and pathological immune cell activation, as well as in immune cell cancers. However, our understanding of the potential consequences of such modulation remains incomplete, partly due to the relative scarcity of information regarding genome-wide ERE transcriptional patterns in immune cells. Here, we describe a methodology that allows probing RNA-sequencing (RNA-seq) data for genome-wide expression of EREs in murine and human cells. Our analysis of B cells reveals that their transcriptional response during immune activation is dominated by induction of gene transcription, and that EREs respond to a much lesser extent. The transcriptional activity of the majority of EREs is either unaffected or reduced by B cell activation both in mice and humans, albeit LINEs appear considerably more responsive in the latter host. Nevertheless, a small number of highly distinct ERVs are strongly and consistently induced during B cell activation. Importantly, this pattern contrasts starkly with B cell transformation, which exhibits widespread induction of EREs, including ERVs that minimally overlap with those responsive to immune stimulation. The distinctive patterns of ERE induction suggest different underlying mechanisms and will help separate physiological from pathological expression.

Journal article

Eksmond U, Jenkins B, Merkenschlager J, Mothes W, Stoye JP, Kassiotis Get al., 2017, Mutation of the putative immunosuppressive domain of the retroviral envelope glycoprotein compromises infectivity, Journal of Virology, Vol: 91, ISSN: 1098-5514

The envelope glycoprotein of diverse endogenous and exogenous retroviruses is considered inherently immunosuppressive. Extensive work mapped the immunosuppressive activity to a highly conserved domain, termed the immunosuppressive domain (ISD), in the transmembrane (TM) subunit of the envelope glycoprotein and identified two naturally polymorphic key residues that afford immunosuppressive activity to distinct envelope glycoproteins. Concurrent mutation of these two key residues (E14R and A20F) in the envelope glycoprotein of the Friend murine leukemia virus (F-MLV) ISD has been reported to abolish its immunosuppressive activity, without affecting its fusogenicity, and to weaken the ability of the virus to replicate specifically in immunocompetent hosts. Here, we show that mutation of these key residues did, in fact, result in a substantial loss of F-MLV infectivity, independently of host immunity, challenging whether associations exist between the two. Notably, a loss of infectivity incurred by the F-MLV mutant with the E14R and A20F double ISD mutation was conditional on expression of the ecotropic envelope receptor murine cationic amino acid transporter-1 (mCAT1) in the virus-producing cell. Indeed, the F-MLV mutant retained infectivity when it was produced by human cells, which naturally lack mCAT1 expression, but not by murine cells. Furthermore, mCAT1 overexpression in human cells impaired the infectivity of both the F-MLV double mutant and the wild-type F-MLV strain, suggesting a finely tuned relationship between the levels of mCAT1 in the producer cell and the infectivity of the virions produced. An adverse effect on this relationship, rather than disruption of the putative ISD, is therefore more likely to explain the loss of F-MLV infectivity incurred by mutations in key ISD residues E14 and A20.

Journal article

Kassiotis G, Stoye JP, 2017, Making a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 372, ISSN: 0962-8436

Like all other mammals, humans harbour an astonishing number of endogenous retroviruses (ERVs), as well as other retroelements, embedded in their genome. These remnants of ancestral germline infection with distinct exogenous retroviruses display various degrees of open reading frame integrity and replication capability. Modern day exogenous retroviruses, as well as the infectious predecessors of ERVs, are demonstrably oncogenic. Further, replication-competent ERVs continue to cause cancers in many other species of mammal. Moreover, human cancers are characterized by transcriptional activation of human endogenous retroviruses (HERVs). These observations conspire to incriminate HERVs as causative agents of human cancer. However, exhaustive investigation of cancer genomes suggests that HERVs have entirely lost the ability for re-infection and thus the potential for insertional mutagenic activity. Although there may be non-insertional mechanisms by which HERVs contribute to cancer development, recent evidence also uncovers potent anti-tumour activities exerted by HERV replication intermediates or protein products. On balance, it appears that HERVs, despite their oncogenic past, now represent potential targets for immune-mediated anti-tumour mechanisms.

Journal article

Jenkins B, Eksmond U, Young G, Kassiotis Get al., 2017, Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein, Wellcome Open Research, Vol: 1, Pages: 22-22

<ns4:p>To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs) of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II), and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of pMHC formation or TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.</ns4:p>

Journal article

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