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Our group studies the biological principles and host interactions that underpin human virus replication and pathogenesis, seeking also to illuminate fundamental aspects of cell function and to pinpoint potential strategies for viral control or eradication. One fruitful approach that we have employed is the analysis of “context-dependent” deficiencies in virus replication.

These may be manifested during the examination of viral mutants/variants, cell-type or species-specific effects, or altered cell culture conditions, and, simplistically, may be attributed either to 1) the lack of cellular dependency factors that promote replication or 2) the presence of natural suppressors (frequently called restriction factors).

Malim

HIV-1 Post-Entry Restrictions. TRIM5alpha and MX2 reside in target cells and block early reverse transcription and viral nuclear import, respectively. APOBEC3 proteins are incorporated into virus particles and interfere with viral replication complexes by editing cDNA via cytidine deamination and suppressing reverse transcription. HIV-1 encodes an antagonist for APOBEC3 proteins, called Vif, but not for TRIM5alpha or MX2.

 

Current PhD students:

Sam Acors

Joseph Ng

Adrian Signell

Nathalia Almeida Dos Santos

People

Sam Acors

PhD Student

Daniel Cox

PhD Student

James Daly

Research Associate

Themes

Malim Lab
Interferon and the Anti-Viral State

A major interest of our recent work has been the interferons, a family of cytokines that act as potent inhibitors of viral replication by elaborating a cellular anti-viral state through the induced expression of interferon-stimulated genes (ISGs). Accordingly, we have been employing cDNA overexpression, gene silencing and proteomic-based approaches to identify ISGs that suppress HIV-1 infection. Through these efforts, we defined the GTPase MX2/MxB as a nuclear envelope associated restriction factor that impedes the nuclear import of viral replication complexes, and the human form of the TRIM5alpha ubiquitin ligase as an immunoproteasome-activated inhibitor of initial post-entry steps of infection. Based on the targeting of pre-integration steps of HIV-1 replication by multiple restriction factors, we conclude that this phase of the virus life cycle is particularly vulnerable to cell-encoded anti-viral suppressors.

    Malim Lab
    APOBEC3 Proteins and HIV-1 DNA Synthesis

    We continue to investigate the HIV-1 inhibitory properties of APOBEC3 proteins, particularly with respect to effects on viral DNA metabolism and how cellular factors can regulate the process of reverse transcription. As a by-product of this work, we have developed protocols for analysing the progression of reverse transcription at single-nucleotide resolution in infected cells, offering opportunities to study the mechanism(s) of action of pharmacologic inhibitors of reverse transcriptase as well as pathways of drug resistance.

      Malim Lab
      Endocytic Virus Entry

      During some of our control experiments with HIV-1 pseudotypes carrying Env proteins from other viruses, we noticed that the interferon-inducible isoform 4 of NCOA7 is able to suppress infection by viruses that enter cells through the endocytic pathway. Stepwise analysis of influenza A virus infection revealed that viral membrane fusion is inhibited (somewhat reminiscent of IFITM3 function), and our current model is that NCOA7 stimulates the vacuolar H+-ATPase leading to acidification of the pathway, protease over-activation and virus inactivation.

        stem cells
        Natural Human Variation and Systems Approaches

        Building upon the concept of inherent (often subtle) human variation giving rise to measurable differences in biological phenotype, the group is embarking on a new collaboration with colleagues in the Centre for Stem Cells & Regenerative Medicine to relate quantitative viral infection phenotypes in panels of closely matched induced pluripotent stem cells (iPSCs) with corresponding -omics datasets as a strategy for uncovering novel cellular regulators of viral infections.

          Alumni

          Postdoctoral Fellows
          Dr James H.M. Simon
          Dr Ron A.M. Fouchier
          Dr Victoria W. Pollard
          Dr Una T. O’Doherty, National Heart, Lung, and Blood Institute, K08 Award
          Dr Ann M. Sheehy, National Institute of Allergy and Infectious Diseases, National Research Service Award, Royal Society U.S.A. Research Fellowship
          Dr Michèle Bouyac-Bertoia
          Dr Yonchu Jenkins, National Institute of Allergy and Infectious Diseases, National Research Service Award
          Dr William J. Swiggard, National Institute of Allergy and Infectious Diseases., K08 Award
          Dr Heather M. Craig
          Dr Kate N. Bishop, Royal Society Dorothy Hodgkin Research Fellowship
          Dr Chad M. Swanson, Research Councils U.K. (RCUK) 5 Year Fellowship
          Dr K. Muneer Ahmad
          Dr Beatrice Kramer
          Dr Hendrik Huthoff, American Foundation for AIDS Research (amfAR) Research Fellowship
          Dr Sarah Gallois-Montbrun, EMBO Long-Term Fellowship
          Dr Fransje Koning, EMBO Long-Term Fellowship
          Dr Nathan M. Sherer, EMBO Long-Term Fellowship
          Dr Flavia Autore, EMBO Short-Term Fellowship
          Dr Kieran Gillick
          Dr Caroline Goujon, Marie Curie Intra-European Fellowship, European Commission
          Dr Hélène Bauby
          Dr Matthew D.J. Dicks
          Dr Lucie Pessel-Vivares
          Dr Darja Pollpeter, Marie Curie International Incoming Fellowship, European Commission

          PhD Students
          Diana Palmeri, Thesis: “Insights into nucleo-cytoplasmic transport mechanisms utilized by retroviral trans-activators”
          Jeffrey D. Dvorin, Thesis: “Trafficking and nuclear import of the HIV-1 pre-integration complex”
          Nathan C. Gaddis, Thesis: “Investigation of the role of Vif in the HIV-1 life cycle”
          Patricia V. Sanchez, Thesis: “Assessment of the contributions of Vpr functions in the HIV-1 replication cycle”
          Chad M. Swanson, Thesis: “Retroviral RNA nuclear export elements regulate protein function and viral assembly”
          Edmund N.C. Newman, Thesis: “Genetic and functional analysis of APOBEC3G: a suppressor of HIV-1 infectivity”
          Rebecca K. Holmes, Thesis: “The antiviral activities of APOBEC proteins”
          Julien R.C. Bergeron, Thesis: “Structural and biochemical study of the Vif-EloBC interaction”
          Prabhjeet K. Phalora, Thesis: “Regulation of APOBEC3 activity and HIV-1 replication by P-body associated proteins”
          Shetal Arjan-Odedra, Thesis: “Regulation of exogenous retroviruses and endogenous retroelements by MOV10”
          Zhisheng Lu, Thesis: “Structural studies of HIV-1 Vif and its SOCS-box domain”
          Tomas Doyle, Thesis: “Mechanisms of the interferon-a induced block to viral replication”
          Christopher C. Ward, Thesis: “The role of human immunodeficiency virus type-1 viral protein R in modifying cellular gene expression early post-infection”

          People

          Sam Acors

          PhD Student

          Daniel Cox

          PhD Student

          James Daly

          Research Associate

          Themes

          Malim Lab
          Interferon and the Anti-Viral State

          A major interest of our recent work has been the interferons, a family of cytokines that act as potent inhibitors of viral replication by elaborating a cellular anti-viral state through the induced expression of interferon-stimulated genes (ISGs). Accordingly, we have been employing cDNA overexpression, gene silencing and proteomic-based approaches to identify ISGs that suppress HIV-1 infection. Through these efforts, we defined the GTPase MX2/MxB as a nuclear envelope associated restriction factor that impedes the nuclear import of viral replication complexes, and the human form of the TRIM5alpha ubiquitin ligase as an immunoproteasome-activated inhibitor of initial post-entry steps of infection. Based on the targeting of pre-integration steps of HIV-1 replication by multiple restriction factors, we conclude that this phase of the virus life cycle is particularly vulnerable to cell-encoded anti-viral suppressors.

            Malim Lab
            APOBEC3 Proteins and HIV-1 DNA Synthesis

            We continue to investigate the HIV-1 inhibitory properties of APOBEC3 proteins, particularly with respect to effects on viral DNA metabolism and how cellular factors can regulate the process of reverse transcription. As a by-product of this work, we have developed protocols for analysing the progression of reverse transcription at single-nucleotide resolution in infected cells, offering opportunities to study the mechanism(s) of action of pharmacologic inhibitors of reverse transcriptase as well as pathways of drug resistance.

              Malim Lab
              Endocytic Virus Entry

              During some of our control experiments with HIV-1 pseudotypes carrying Env proteins from other viruses, we noticed that the interferon-inducible isoform 4 of NCOA7 is able to suppress infection by viruses that enter cells through the endocytic pathway. Stepwise analysis of influenza A virus infection revealed that viral membrane fusion is inhibited (somewhat reminiscent of IFITM3 function), and our current model is that NCOA7 stimulates the vacuolar H+-ATPase leading to acidification of the pathway, protease over-activation and virus inactivation.

                stem cells
                Natural Human Variation and Systems Approaches

                Building upon the concept of inherent (often subtle) human variation giving rise to measurable differences in biological phenotype, the group is embarking on a new collaboration with colleagues in the Centre for Stem Cells & Regenerative Medicine to relate quantitative viral infection phenotypes in panels of closely matched induced pluripotent stem cells (iPSCs) with corresponding -omics datasets as a strategy for uncovering novel cellular regulators of viral infections.

                  Alumni

                  Postdoctoral Fellows
                  Dr James H.M. Simon
                  Dr Ron A.M. Fouchier
                  Dr Victoria W. Pollard
                  Dr Una T. O’Doherty, National Heart, Lung, and Blood Institute, K08 Award
                  Dr Ann M. Sheehy, National Institute of Allergy and Infectious Diseases, National Research Service Award, Royal Society U.S.A. Research Fellowship
                  Dr Michèle Bouyac-Bertoia
                  Dr Yonchu Jenkins, National Institute of Allergy and Infectious Diseases, National Research Service Award
                  Dr William J. Swiggard, National Institute of Allergy and Infectious Diseases., K08 Award
                  Dr Heather M. Craig
                  Dr Kate N. Bishop, Royal Society Dorothy Hodgkin Research Fellowship
                  Dr Chad M. Swanson, Research Councils U.K. (RCUK) 5 Year Fellowship
                  Dr K. Muneer Ahmad
                  Dr Beatrice Kramer
                  Dr Hendrik Huthoff, American Foundation for AIDS Research (amfAR) Research Fellowship
                  Dr Sarah Gallois-Montbrun, EMBO Long-Term Fellowship
                  Dr Fransje Koning, EMBO Long-Term Fellowship
                  Dr Nathan M. Sherer, EMBO Long-Term Fellowship
                  Dr Flavia Autore, EMBO Short-Term Fellowship
                  Dr Kieran Gillick
                  Dr Caroline Goujon, Marie Curie Intra-European Fellowship, European Commission
                  Dr Hélène Bauby
                  Dr Matthew D.J. Dicks
                  Dr Lucie Pessel-Vivares
                  Dr Darja Pollpeter, Marie Curie International Incoming Fellowship, European Commission

                  PhD Students
                  Diana Palmeri, Thesis: “Insights into nucleo-cytoplasmic transport mechanisms utilized by retroviral trans-activators”
                  Jeffrey D. Dvorin, Thesis: “Trafficking and nuclear import of the HIV-1 pre-integration complex”
                  Nathan C. Gaddis, Thesis: “Investigation of the role of Vif in the HIV-1 life cycle”
                  Patricia V. Sanchez, Thesis: “Assessment of the contributions of Vpr functions in the HIV-1 replication cycle”
                  Chad M. Swanson, Thesis: “Retroviral RNA nuclear export elements regulate protein function and viral assembly”
                  Edmund N.C. Newman, Thesis: “Genetic and functional analysis of APOBEC3G: a suppressor of HIV-1 infectivity”
                  Rebecca K. Holmes, Thesis: “The antiviral activities of APOBEC proteins”
                  Julien R.C. Bergeron, Thesis: “Structural and biochemical study of the Vif-EloBC interaction”
                  Prabhjeet K. Phalora, Thesis: “Regulation of APOBEC3 activity and HIV-1 replication by P-body associated proteins”
                  Shetal Arjan-Odedra, Thesis: “Regulation of exogenous retroviruses and endogenous retroelements by MOV10”
                  Zhisheng Lu, Thesis: “Structural studies of HIV-1 Vif and its SOCS-box domain”
                  Tomas Doyle, Thesis: “Mechanisms of the interferon-a induced block to viral replication”
                  Christopher C. Ward, Thesis: “The role of human immunodeficiency virus type-1 viral protein R in modifying cellular gene expression early post-infection”