Human cytomegalovirus (HCMV) is a betaherpesvirus that infects most humans worldwide. In the healthy host, it elicits a broad immune response involving both the innate and adaptive arms of immunity, which is able to limit viral replication and prevent end-organ disease. However, like all herpesviruses, the virus then establishes a lifelong latent infection such that the host is unable to eradicate the virus completely. This then results in periods during which the virus reactivates and can replicate. In an immunocompetent host, this replication is eventually controlled by a robust secondary immune response. However, when this occurs during periods of immunosuppression, such as after solid organ or haematopoietic stem cell transplantation, the virus is then able to multiply rapidly and infect numerous organ systems. Consequently, HCMV is one of the most frequently-occurring viral infections in such patients. Most of the previous studies on HCMV infections in these patients have focused on the CD8+ T cell response, but in recent years, more evidence has come to light that other immune cell populations play a role as well.

In the work presented in this thesis, I have utilised a viral dissemination assay (VDA) to study the responses of peripheral blood mononuclear cells (PBMCs), CD4+ cells, CD8+ T cells, and natural killer (NK) cells to HCMV infection of autologous fibroblasts in healthy HCMV-seropositive and HCMV-seronegative adults, and showed that there were inherent differences in the ability to control HCMV immediate-early (IE) and late gene expression between the PBMCs, CD4+ cells and CD8+ T cells from HCMV-seropositive and HCMV-seronegative individuals. It was also found that the presence of other immune cells in a CD4+ cell population, such as CD14+ monocytes, are essential for CD4+ T cells to recognise HCMV-infected fibroblasts via the MHC Class II antigen presentation pathway. This leads to the production of a cytokine milieu that can limit HCMV dissemination, of which IFN-γ was found to be one of the key cytokines. A small number of plasmacytoid dendritic cells were also present in the CD4+ cell population, although their contribution to overall control by CD4+ cells is yet to be fully determined.

I have also used the VDA to assess the responses of PBMCs, CD4+ cells, CD8+ T cells, and NK cells from kidney and liver transplant patients to HCMV-infected autologous fibroblasts, and shown that this assay may provide a more comprehensive assessment of the immune response to HCMV than measurement of interferon-γ responses of T cells to HCMV peptides, a commonly used method of immune monitoring in these patient groups. I have also compared the responses of the transplant patients to those from healthy adults, and shown that, during periods of CMV viraemia, patients frequently have responses similar to or worse than those from HCMV-seronegative adults, regardless of the HCMV serostatus of the donor or recipient.