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Prof Greg Towers

Prof Greg Towers

Blue and yellow HIV-2 on 293T SEM

Our work aims to understand the molecular details of host virus interactions. We focus on human immunodeficiency virus type 1, the cause of AIDS in humans, but we also study other primate lentiviruses expecting comparing viruses from different species to be informative. Currently, a favorite question is How does the HIV-1 capsid regulate encapsidated DNA synthesis to evade innate immune nucleic acid sensors? We also study other viruses, particularly flaviviridae and Hepatitis B virus, which we hypothesise cloak their replication from innate sensors in a similar way to HIV-1. We study host virus interactions because we believe that the new knowledge we find will be valuable in many ways. For example, we expect that a more detailed understanding of host virus interactions will help us to drug viral infection experimentally and therapeutically. We are developing three series of novel inhibitors of viral infection that manipulate viruses’ ability to hide from innate immune pattern recognition receptors. We also aim to use our understanding of innate immune control of HIV-1 to develop novel gene therapy based approaches to treat HIV-1 infection and to improve the utility of current HIV based gene delivery systems.

We believe that viruses are very good cell biologists and by working out how they interact with their hosts we will discover new understanding of host cell processes. Thus, we believe that one cannot truly appreciate the relationship between host and virus without a sound understanding of evolution. This is best illustrated by Lee Van Valen’s Red Queen hypothesis, which suggests that host and pathogen are locked in a genetic conflict in which both host and virus are obliged to continually evolve with each alternately gaining and losing the advantage. Understanding this process promises to enable prediction of zoonosis and pandemicity.

We also study host virus interactions because it is a very competitive and well-funded area of research that is really good fun to work in.

 


    Postdocs and Senior Scientists

    Dr Lucy Thorne

    Dr Lucy Thorne
    I am a Sir Henry Wellcome Postdoctoral Research Fellow in the Towers lab. My research is focussed on understanding the viral and host factors that determine whether HIV-1 is sensed and restricted by the innate immune response. To an incoming virus, the host cell cytoplasm is a hostile environment, full of sensors that can detect viral components and initiate an innate immune response capable of suppressing infection. Cytoplasmic DNA sensors present a particular challenge to HIV-1 in the early stages of its lifecycle when it must make new viral DNA whilst crossing the cytoplasm. Previous work in the Towers lab has shown that the incoming HIV-1 capsid core recruits host cell proteins to its outer surface, which can act as a cloak to prevent sensing of the viral DNA in the cytoplasm (Rasaiyah et al. Nature 2013). One of these host proteins is cyclophilin A (CypA), which is also used as a cofactor by an array of different viruses. We do not yet fully understand the cellular role of CypA, how its interaction with the HIV-1 core prevents DNA sensing, or the broad-antiviral mechanism of CypA inhibitors. One aspect of my research aims to understand the mechanism by which recruitment of CypA enables evasion of the innate immune response and whether this is a strategy broadly employed by other viruses. Prior to joining the Towers lab I completed my PhD and a postdoc position in the lab of Prof Ian Goodfellow (University of Cambridge), where my research was focused on characterising norovirus replication and host-cell interactions.

    Dr Morten Govasli Larsen

    Dr Morten Govasli Larsen
    I am a biochemist with experience in recombinant protein production, and structural biology using nuclear magnetic resonance spectroscopy (NMR) supported by multiple biophysical techniques. I am employing these methods to investigate the relationship between primate lentiviruses and their cofactors. A key goal is to understand whether cofactor interactions differ between different primate lentiviruses and whether comparative virology can help us understand cofactor function. I'm also keen to understand the molecular mechanisms of capsid inhibitors and the role of cofactor binding in the inhibitory process.

    Dr Maorong Xie

    Dr Maorong Xie (photo curtesy of Kelvin Vine)
    I undertook my PhD in the lab of Prof. Serge Benichou working on HIV-1 cell-to-cell transfer and viral dissemination in myeloid cells. My current work in the Towers lab aims to understand the manipulation of host cells by HIV-1 and other primate lentiviruses, with a particular focus on viral accessory proteins, Vpr and Vpx. HIV has evolved multiple strategies to evade innate immune responses and to counteract host restriction factors with a lot help from viral accessory proteins. However, host cells have also developed molecular pathways that recognize proviral DNA and mediate transcriptionally silencing of invading retroviruses. This arms race between host and cells involves viral escape mechanisms and the host innate immune response. A better understanding of this process promises to enable better anti-viral drug design and more effective HIV-based gene therapy strategies.

    Dr Dara Davison

    Dr Dara Davison
    From a background in chemistry, I completed a PhD with Dr Edgar Deu at The Francis Crick Institute, where I used chemical proteomics to investigate the malaria-causing parasite Plasmodium falciparum. As a postdoctoral researcher in the Tower’s lab I am working with clinicians at Great Ormond Street Hospital to improve the efficiency of gene therapy. Gene therapy is used to treat rare genetic disorders, for example severe combined immunodeficiency (SCID). In these cases, patient stem cells are treated in vitro with a viral vector to deliver a correct copy of the defective gene and then replaced in the patient. These treatments can provide long-term relief but are costly, as viral infection of stem cells is inefficient and requires a lot of viral vector. We have identified a protein called IFITM3 that appears to protect stem cells from viral infection. My project involves investigating molecules that cause the degradation of IFITM3 and therefore improve gene therapy efficiency.  We will also use the tools that we develop, along with proteomics techniques, to investigate the underlying mechanisms involved and how IFITM3 plays its crucial role in innate immunity.

     

    Dr Jaskaren Kohli

    Dr Jaskaren kohli

    My career thus far has focused on the study of cellular senescence and its relationship to cancer and ageing. In Dr. Marco Demaria's lab (University Medical Centre Groningen, Netherlands) on an individual Marie-Curie fellowship, I showed that senescent skin cells switch on anti-apoptotic pathways to maintain their own viability, and pharmacological inhibition can sensitise senescent cells to die. This may be beneficial in preventing onset of skin cancer.  Senescence has also been associated with innate immune activation. I would like to understand how this relationship works and whether senescence and senescence associated innate immune activation influences permisivity to viral infection, and perhaps more importantly, influences the inflammatory response to infection. For example, do higher levels of senescent cells in the elderly influence the outcome of infectious diseases? An obvious exemplar is SARS-CoV-2 which causes inflammatory disease, particularly in the elderly and I am looking forward to dissecting these relationships and learning some virology.

    Dr Ying Ying Tan

    Dr Ying Ying Tan
    With a multidisciplinary background in immunopharmacology and organic chemistry, I completed my PhD at Imperial College London with Prof. Masao Takata where I investigated the roles of extracellular vesicles in the pathophysiology of Acute respiratory Distress Syndrome (ARDS). The recent outbreak of the COVID-19 pandemic resulting in severe ARDS has motivated my research interest in virology, especially how pandemic-causing viruses such as SARS-CoV-2 and HIV-1 have evolved to evade innate immune sensing and cause severe inflammatory diseases. There has been growing evidence that viruses exploit epigenetics processes in order to dysregulate cellular pathways and to optimise their own replication. Utilising HIV-1 and SARS-CoV-2 as viral infection models, my current work in the Towers lab focuses on the mechanism of epigenetics (dys)regulation during viral infection with a particular focus on the repression and derepression of transposable elements (also known as “jumping genes”).

    Dr Giulia Dowgier

    Dr Giulia Dowgier
    I am a Postdoctoral Research Fellow supported by the G2P-UK National Virology Consortium, a UKRI funded virology network studying the effects of emerging SARS-CoV-2 variants on transmission, disease severity, and vaccine effectiveness. Defining the strategies that SARS-CoV-2 variants adopt to evade and antagonise host immune responses is crucial in understanding viral transmission and pathogenesis as well as selection pressures driving evolution of a recently zoonotic virus. My goal is to dissect the role of specific adaptations within emerging SARS-CoV-2 variants using in vitro models of infections and reverse genetics to study infectious virus. I have experience working on animal coronaviruses through a PhD studying Canine Coronavirus (CCoV), and a postdoc in Erica Bickerton’s lab at The Pirbright Institute. Here I focussed on using synthetic biology and reverse genetics to develop rationally attenuated vaccines against infectious bronchitis virus (IBV), an avian coronavirus. I also studied IBV pathogenesis in poultry and worked with Porcine Respiratory Coronavirus (PRCV) as a model for SARS-CoV-2.

    Dr Doug Fink

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    I am currently an NIHR academic clinical lecturer at LSHTM. I completed a Wellcome Trust funded PhD in the Towers lab in 2019. I also work in the NHS as an infectious diseases doctor. My PhD thesis sought to characterise the modulation of innate immune signalling by lentiviral accessory protein vpx. In my post-doctoral work I am collaborating with the Towers lab to develop observations from my PhD relating to epigenetic regulation of endogenous retroelements and innate immunity. In parallel I am committed to developing clinical and research infrastructure in low and middle income settings. I have a long-standing collaboration with the Nigerian Institute of Medical Research in Lagos studying non-communicable disease in people living with HIV. I teach on both the London and East African Diplomas of Hygiene and Tropical Medicine, besides undergraduate and postgraduate programmes at LSHTM and UCL. I am heavily involved with BHIVA and am chair of the International Partnership working group.

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    Dr John Walter

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    Resident Artist in Infection
    ​Dr ​ John Walter is an artist and academic working in a diverse range of media that includes drawing, painting, printmaking, sculpture, digital imaging, video, performance and installation. His PhD 'Alien Sex Club:  Educating audiences about continuing rates of HIV transmission using art and design' addressed​ ​HIV as a crisis of representation for visual art. ​He won the Hayward Curatorial Open in 2016 for 'Shonky: The Aesthetics of Awkwardness', which toured from The MAC Belfast to DCA Dundee and Bury Art Gallery and Sculpture Centre. His collaboration with Greg Towers on 'CAPSID' is supported by a Wellcome Trust Large Arts Award. His work as artist in residence in the lab has resulted in over 250 artworks, which form an exhibition at CGP London and HOME Manchester along with a monograph published by HOME.

    Dr Chris van Tulleken

    Dr Chris van Tulleken

    I undertook my PhD in the Towers lab working on lentiviral Vpr proteins. I am now working as an infection doctor at UCLH and an occasional science presenter for the BBC often with the help of the Towers lab. I maintain links with the Towers lab through my position as a Honorary Senior Lecturer at UCL. I’m still on the Vpr team and help on the lab's wide ranging outreach projects.

     

     

    PhD Students

    Dr Rob Lever

    Dr Rob Lever
    I am an Infectious Diseases doctor currently undertaking a Wellcome Trust Clinical Research Training Fellowship in the Towers Laboratory. My research is focussed on understanding the functions and roles of lentiviral accessory proteins, particularly Vpr and Vpx. Retroviruses are phenomenally successful in infecting a variety of species despite having a limited number of genes. As such each accessory gene fulfils a variety of functions, primarily in the antagonization of the vertebrate immune system. Investigating the interaction of these viral proteins with vertebrate cells, and their differences between species, is a unique method for studying a wide range of cellular processes; from the initiation of an innate immune response to the control of transcription at the epigenetic level. In addition to my work in the lab I teach on a variety of undergraduate medical and science courses at UCL and have previously lead several large clinical research studies at the Hospital for Tropical Diseases.

    Lydia Newton

    Lydia Newton, PhD student 2021
    I am PhD student on the UCL-Birkbeck MRC Doctoral Training Programme. In collaboration with Professor Flemming Hansen (Institute of Structural and Molecular Biology), I am undertaking a PhD project in the Towers lab studying NS5A from hepatitis C virus (HCV). This protein is essential for many aspects of the HCV life cycle, including genome replication and virus particle assembly. Existing therapies in widespread clinical include direct acting antivirals (DAAs), which are believed to target NS5A. These drugs are exceptionally potent, exhibiting picomolar activities, however their exact mechanisms of action remain unknown. Using an interdisciplinary approach combining cell biology and biophysical techniques, I aim to further understand the therapeutic activity of these NS5A inhibitors. HCV replicon assays and nuclear magnetic resonance (NMR) experiments will be employed to characterise the binding of DAAs to NS5A. This research will be important both in the treatment of HCV and the design of drugs targeting other proteins.

     

    Kate Morling

    Kate Morling
    I am a PhD student on the Institute of Structural and Molecular Biology PhD programme investigating molecules which manipulate viral infectivity. In collaboration with the Selwood group, I am working on enhancing the efficiency of lentivirus-based gene delivery in stem cell gene therapy. Due to stem cell innate immunity, large amounts of costly viral vector and lengthily cell cultures are currently required. We have identified molecules which induce degradation of antiviral factor IFITM3, shutting off the cell’s defence against viral infection. I am using proteolysis targeting chimeras (PROTACs) to investigate how these molecules induce IFITM3 degradation and the underlying mechanism of IFITM3 restriction, which remains poorly understood. In addition, I am working on a series of molecules termed allosteres which inhibit the HIV capsid, a protective shell which encases the viral genome and shields it from innate immune nucleic acid sensors. Through a combination of chemical, structural and cell biology, I hope to develop allosteres with increased potency, characterise their mechanism of action, and utilise them as tools to probe capsid function.

     

     

     

    Lab Manager

    Jane Turner

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