Abstract
Natural killer (NK) cells are a critical component of the innate immune response to viral
infection. NK cells are responsible for the early control of virus spread, cytolytically killing
infected cells, as well as secreting proinflammatory cytokines to enhance immune responses.
In patients with deficiencies in NK cell function, there is an extreme susceptibility to infection
with herpesviruses, in particular, varicella zoster virus (VZV) and herpes simplex virus type 1
(HSV-1). These two medically important human alphaherpesviruses cause widespread
disease in human hosts, with VZV being the causative agent of varicella (chickenpox) and
herpes zoster (shingles), while HSV-1 causes recurrent orolabial lesions (cold sores). Both
viruses have the potential to cause severe complications, such as encephalitis and debilitating
nerve pain. The vital role that NK cells play in controlling VZV and HSV-1 infections denotes an
intricate struggle for dominance between virus and NK cell antiviral immunity; however,
research in this area has remained surprisingly limited. This thesis explored the interactions
between human NK cells and alphaherpesviruses, examining NK cell recognition of infected
cells, as well as investigating viral infection of NK cells and manipulation of their function. Investigation into alphaherpesvirus interactions with NK cells first focused on examining
whether VZV and HSV-1 modulated the surface of infected cells to potentially regulate NK cell
recognition. In vitro co-culture of NK cells with VZV infected cells revealed that NK cells did not
display enhanced activation in response to the infection, suggesting that specific viral
mechanisms to limit NK cell detection may be at play. Delving into this, the expression of four
specific ligands (MICA, ULBP1–3) recognised by the activating NK cell receptor, NKG2D, were
examined during viral infection. Comparing VZV and HSV-1, differential patterns of regulation
were found between the two viruses, as well as between distinct NKG2D ligands. Given that VZV appeared to be evading NK cell recognition, the research focus then turned to
investigating how VZV directly interacted with NK cells. VZV is established as a lymphotropic
virus, using the infection of immune cells to disseminate virus around the body, however it
has so far remained unknown whether NK cells are permissive to VZV infection. Examination
of human peripheral blood NK cells revealed that VZV productively infected NK cells,
facilitating transmission of infectious virus to other cells in culture. VZV preferentially infected
mature NK cell populations, as well as modulating cell-surface expression of maturityassociated
markers. Notably, VZV infection of NK cells led to upregulated expression of
chemokine receptors implicated in trafficking to the skin, suggesting that NK cells may play a
key role in VZV pathogenesis. As NK cells were permissive to productive VZV infection, the effect of VZV on NK cell function
was then investigated. Assessing cytolytic function, it was found that co-culture with VZV lead
to potent inhibition of NK cell responsiveness to target cell stimulation. Remarkably, not only
were VZV infected NK cells impaired, but also NK cells exposed to virus were inhibited without
needing to progress to full productive infection. HSV-1 had a similar capacity to paralyse NK
cell cytolytic function, identifying a powerful immune evasion strategy shared by both
alphaherpesviruses. In contrast, when NK cell cytokine responses were investigated,
differential targeting of cytokine production was demonstrated between VZV and HSV-1.
Overall, this thesis illuminates the complex interactions that occur between viral infection and
the immune response. The findings presented in this thesis enhance our understanding of
how viruses like VZV and HSV-1 are able to evade the immune system to establish lifelong
infections, as well as furthering our understanding of how viruses can shape and manipulate
the immune response.
