Malim Lab

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).

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

Members

Gilberto Jose Betancor Quintana

Research Associate

Liane Dupont

Research Associate

Jose M. Jimenez-Guardeño

Research Fellow

Michael Malim

Professor of Infectious Diseases

Ana Maria Ortega-Prieto

Research Associate

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.

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.

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.

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.

Sheehy, A.M., Gaddis, N.C., Choi, J.D. and Malim, M.H. (2002). Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418, 646-650. Harris, R.S., Bishop, K.N., Sheehy, A.M., Craig, H.M., Petersen-Mahrt, S.K., Watt, I.N., Neuberger, M.S. and Malim, M.H. (2003). DNA deamination mediates innate immunity to retroviral infection. Cell 113, 803-809. Sherer, N.M., Swanson, C.M., Hué, S., Roberts, R.G., Bergeron, J.R.C. and Malim, M.H. (2011). Evolution of a species-specific determinant within human CRM1 that regulates the post-transcriptional phases of HIV-1 replication. PLoS Pathogens 7, e1002395. Goujon, C., Moncorgé, O., Bauby, H., Doyle, T., Ward, C.C., Schaller, T., Hué, S., Barclay, W.S., Schulz, R. and Malim, M.H. (2013). Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 502, 559-562. Apolonia, L., Schulz, R., Curk, T., Rocha, P., Swanson, C.M., Schaller, T., Ule, J. and Malim, M.H. (2015). Promiscuous RNA binding ensures effective encapsidation of APOBEC3 proteins by HIV-1. PLoS Pathogens 11, e1004609. Lorenzo-Redondo, R., Fryer, H.R., Bedford, T., Kim, E.-Y., Archer, J., Kosakovsky Pond, S.L., Chung, Y.-S., Penugonda, S., Chipman, J.G., Fletcher, C.V., Schacker, T.W., Malim, M.H., Rambaut, A., Haase, A.T., McLean, A.R. and Wolinsky, S.M. (2016). Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 530, 51-56. Pollpeter, D., Parsons, M., Sobala, A.E., Coxhead, S., Lang, R., Bruns, A.M., Papaioannou, S., McDonnell, J.M., Apolonia, L., Chowdhury, J., Horvath, C.M. and Malim, M.H. (2018). Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted anti-viral functions of APOBEC3G. Nature Microbiology 3, 220-233. Doyle, T., Moncorgé, O., Bonaventure, B., Pollpeter, D., Lussignol, M., Tauziet, M., Apolonia, L., Catanese, M.-T. Goujon, C. and Malim, M.H. (2018). The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry. Nature Microbiology 3, 1369-1376. Dicks, M.D.J., Betancor, G., Jimenez-Guardeño, J.M., Pessel-Vivares, L., Apolonia, L., Goujon, C., and Malim, M.H. (2018). Multiple components of the nuclear pore complex interact with the amino-terminus of MX2 to facilitate HIV-1 restriction. PLoS Pathogens 14, e1007408. Jimenez-Guardeño, J.M., Apolonia, L., Betancor, G. and Malim, M.H. (2019). Immunoproteasome activation enables human TRIM5 restriction of HIV-1. Nature Microbiology 4, 933-940.

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”

Malim Lab