Human cytomegalovirus (HCMV) is a paradigm for viral immune evasion strategies yet, paradoxically, primary infection of immunocompetent individuals rarely causes serious disease and such primary infections are normally quickly resolved. In contrast, infection of individuals whose immune systems are compromised (such as HIV/AIDS patients and transplant patients) or immature (such as the foetus in utero) often leads to wide spread viral replication and dissemination and this can often be life threatening. Although the immune evasion mechanisms employed by HCMV in vitro are well documented, the effectiveness of these during primary infection in vivo is not absolutely clear but probably allow the pathogen to initially overcome primary immune responses and thus create a window of opportunity for the virus to replicate and disseminate to cell types efficiently enough for latency to be established. Such a strategy could be conceived to be optimal for a life-long persistent pathogen as unchecked viral replication, leading to host mortality, would clearly be a dead end strategy for any virus. However, the establishment of quiescence would also, in itself, be a biological dead end for the virus, unless it was able to reactivate and re-establish lytic infection in order to infect naïve individuals. Similarly, a fitting time for a comprehensive set of immunevasion functions to be employed by the virus would be during reactivation from latency; these would again create a window of opportunity for the virus to re-establish the production of new virions in the face of an existing and primed anti-viral immune response.
Our programme of research seeks to addressed a number of important questions concerning the immunobiology of HCMV both in lytic and during latent infection. With a particular focus on the generation, maintanance and funtion of memory CD4+ and CD8+ T cells and the immune evasion mechanism employed by the virus to modulate Natural Killer cell function.
Jackson SE, Chen KC, Groves IJ, Sedikides GX, Gandhi A, Houldcroft CJ, Poole EL, Montanuy I, Mason GM, Okecha G, Reeves MB, Sinclair JH, Wills MR.Latent Cytomegalovirus-Driven Recruitment of Activated CD4+ T Cells Promotes Virus Reactivation. Front Immunol. 2021 Apr 12;12:657945. doi: 10.3389/fimmu.2021.657945. eCollection 2021.PMID: 33912186
Collier DA, …………, Wills M, Veesler D, Corti D, Gupta RK Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature. 2021 May;593(7857):136-141. doi: 10.1038/s41586-021-03412-7. Epub 2021 Mar 11.PMID: 33706364
Groves IJ, Jackson SE, Poole EL, Nachshon A, Rozman B, Schwartz M, Prinjha RK, Tough DF, Sinclair JH, Wills MR.Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention. Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):e2023025118. doi: 10.1073/pnas.2023025118.PMID: 33619107
Vlahava VM, Murrell I, Zhuang L, Aicheler RJ, Lim E, Miners KL, Ladell K, Suárez NM, Price DA, Davison AJ, Wilkinson GW, Wills MR, Weekes MP, Wang EC, Stanton RJ Monoclonal antibodies targeting nonstructural viral antigens can activate ADCC against human cytomegalovirus.J Clin Invest. 2021 Feb 15;131(4):e139296. doi: 10.1172/JCI139296.PMID: 33586678
Houldcroft CJ, Jackson SE, Lim EY, Sedikides GX, Davies EL, Atkinson C, McIntosh M, Remmerswaal EBM, Okecha G, Bemelman FJ, Stanton RJ, Reeves M, Wills MR. Assessing Anti-HCMV Cell Mediated Immune Responses in Transplant Recipients and Healthy Controls Using a Novel Functional Assay. Front Cell Infect Microbiol. 2020 Jun 26;10:275. doi: 10.3389/fcimb.2020.00275. eCollection 2020.PMID: 32670891
Killer cell proteases can target viral immediate-early proteins to control human cytomegalovirus infection in a noncytotoxic manner. Shan L, Li S, Meeldijk J, Blijenberg B, Hendriks A, van Boxtel KJWM, van den Berg SPH, Groves IJ, Potts M, Svrlanska A, Stamminger T, Wills MR, Bovenschen N. *Joint corresponding authors PLoS Pathog. 2020 Apr 13;16(4):e1008426. doi: 10.1371/journal.ppat.1008426. eCollection 2020 Apr.PMID: 32282833
Fares S, Spiess K, Olesen ETB, Zuo J, Jackson S, Kledal TN, Wills MR, Rosenkilde MM.Distinct Roles of Extracellular Domains in the Epstein-Barr Virus-Encoded BILF1 Receptor for Signaling and Major Histocompatibility Complex Class I Downregulation. MBio. 2019 Jan 15;10(1). pii: e01707-18. doi: 10.1128/mBio.01707-18.Genomics. 2018 Aug 2;19(1):577. doi: 10.1186/s12864-018-4949-6.PMID: 30068288
Jackson SE, Sedikides GX, Okecha G, Poole EL, Sinclair JH, Wills MR. Latent Cytomegalovirus (CMV) Infection Does Not Detrimentally Alter T Cell Responses in the Healthy Old, But Increased Latent CMV Carriage Is Related to Expanded CMV-Specific T Cells. Front Immunol. 2017 Jun 26;8:733. doi: 10.3389/fimmu.2017.00733. 2017.
Jackson SE, Sedikides GX, Mason GM, Okecha G, Wills MR. HCMV Specific CD4+ T Cells are poly-functional and can respond to HCMV Infected Dendritic Cells in vitro. J Virol. 2017 Jan 4. pii: JVI.02128-16. doi: 10.1128/JVI.02128-16. PMID: 28053099
Chen KC, Stanton RJ, Banat JJ, Wills MR. Leukocyte Immunoglobulin-Like Receptor 1-Expressing Human Natural Killer Cell Subsets Differentially Recognize Isolates of Human Cytomegalovirus through the Viral Major Histocompatibility Complex Class I Homolog UL18.J Virol. 2016 Jan 6;90(6):3123-37. doi: 10.1128/JVI.02614-15.
Jackson SE, Mason GM, Okecha G, Sissons JG, Wills MR. Diverse specificities, phenotypes, and antiviral activities of cytomegalovirus-specific CD8+ T cells. J Virol. 2014 Sep;88(18):10894-908.
Gavin M Mason, Sarah Jackson, Georgina Okecha, Emma Poole, J.G. Patrick Sissons, John Sinclair and Mark R Wills. 2013. Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4+ T cells. PlosPathogens 2013;9(10):e1003635
Mason, G. M., E. Poole, J. G. Sissons, J. H. Sinclair, and M. R. Wills. 2012. Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+ T-cell migration and suppression of effector function. Proceedings of the National Academy of Sciences of the United States of America 4;109(36):14538-43.
Bennett NJ, Ashiru O, Morgan FJ, Pang Y, Okecha G, Eagle RA, Trowsdale J, Sissons JG, Wills MR(2010) Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus J ImmunolJul 15; 185(2): 1093-102
Ashiru O, Bennett NJ, Boyle LH, Thomas M, Trowsdale J, Wills MR (2009) NKG2D ligand MICA is retained in the cis-Golgi apparatus by human cytomegalovirus protein UL142 J Virol Dec; 83(23): 12345-54