Download T cell targeting of latent cytomegalovirus infected cells: can viral

T cell targeting of latent cytomegalovirus infected cells: can viral latency be
eliminated?
Supervisor:
Dr Mark Wills
Project code for applications: SCM039
Abstract:
Human Cytomegalovirus (HCMV) is a pathogen that can cause significant morbidity and
mortality, particularly in the immunocompromised or immunonaive. HCMV disease is
regularly seen after primary infection of individuals with an underdeveloped or suppressed
immune system, such as transplant patients or those suffering with AIDS. Similarly, infection
in utero, in the developing immunonaive foetus, can result in mental retardation, deafness
and blindness. In individuals with competent immune systems, however, primary HCMV
infection rarely causes disease and this is likely due to the well-established robust immune
response to the virus.
Despite this rigorous host immune control, HCMV is never cleared after primary infection
but, like all herpesviruses, persists for the lifetime of the host and this life-long persistence is
facilitated by the ability of the virus to establish a latent infection in which virus is carried
silently in certain cell types, in the absence of virus DNA replication or new virion
production. Consequently, current therapies for HCMV, which target virus replicating
productively, will not target latent viral genomes. Yet reactivation of virus production from
these latent virus pools is a major cause of disease in immune suppressed transplant
patients.
We have recently demonstrated that the HCMV is able to manipulate the myeloid CD34+
progenitor cells that it latently infects to provide an immunosuppressive microenvironment
to prevent T cell recognition and killing of the latently infected cell (Mason et al, 2012). In
addition we have shown that at least two viral proteins known to be expressed during
latency (UL138 and LUNA) are targets for host CD4+ T cells (Mason et al 2013) and have
established that other viral genes (US28, LAcmvIL-10 encoded in UL111A and UL144) are
also expressed during latent infection and, as such, could also be immunological targets for
host T cells. Consequently, it is possible that immunological clearance of latent viruses could
be attainable if latently expressed viral gene products could be efficiently targeted by these
host T cell responses.
Both LUNA and UL138 elicit CD4+ Th 1 -type responses, characterised by IFNϒ production and
UL138, but not LUNA, specific CD4+ T cells can mediate MHC class II restricted cytotoxicity.
Intriguingly, a proportion of the UL138 and LUNA specific CD4+ T cells also secreted the
immunomodulatory cytokines cellular interleukin-10 (cIL-10) and Transforming Growth
Factor β (TGF-β) and this may help explain why T cell recognition of UL138 and LUNA, in
vivo, does not lead to these cells elimination.
We hypothesise that T cell responses to US28, UL111A and UL144 will also be generated and
may also be dominated by cIL-10 producing T cells. This PhD will investigate the CD4 and
CD8 T cell responses to these latently expressed proteins, establish if they also generate
regulatory T cells and using an in vitro model of HCMV latency investigate strategies to
modulate regulator cytokines and T cells in order to allow anti-viral T cell recognition of cells
and elimination of the latent cell reservoir. The project will involve the use of cutting edge T
cell analysis techniques by flowcytometry, multi-analyte cytokine detection, peptide
mapping of CD4 and CD8 T cell responses and virological assays for anti-viral T cell activity.
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 Oct;9(10).
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.