This project investigates the potential of Natural Killer (NK) cells to respond to pathogen
associated molecular patterns (PAMP) as model adjuvants and establishes the potential of
PAMP to aid the recovery of antigen specific T-cell responses in chronic HIV-1 infection.
Innate immunity is mediated by through the recognition of conserved PAMP recognised by
receptors such as the toll-like receptors (TLR), expressed by accessory cells including
blood DC, which are responsible for initiating adaptive immune responses, but also
activate NK cells. NK cells are no longer seen solely as killers, but instead produce
cytokines, including IFN-γ, and participate in the generation of adaptive immune responses
with DC.
HIV-1 infection potentially chronically activates TLR pathways, via recognition of the viral
genome and as a result of damage to mucosal surfaces leading to microbial translocation
and systemic recognition of PAMP including bacterial lipopolysaccharides. NK cell
activation, cytokine production, differentiation and proliferation in response to PAMP have
therefore been examined. NK cell responsiveness to certain TLR agonists was refractory
in HIV-1 infected individuals although responses were maintained within CD56+CD16- NK
cells, potentially providing help for antigen specific T-cell responses. The effects of HIV-1
infection on NK cell maturation were also investigated.
T-cell activation by TLR agonists was also refractory in HIV-1 infected individuals. The
impact of TLR ligation on antigen specific T-cell responses was investigated, combining
TLR agonists with peptide pools (influenza, Epstein-Barr virus and cytomegalovirus or
HIV-1 gag antigens). Of the TLR agonists tested, only CpG DNA resulted in enhanced
frequencies of IFN-γ producing T-cells in HIV-1 infected individuals, whereas LPS
demonstrated consistently reduced IFN-γ production.
In conclusion, maintenance of responsiveness of CD56+CD16- NK cells and enhancement
of HIV-1 antigen specific T-cell responses by CpG DNA have implications for both
repopulation of the NK cell compartment and reconstitution of acquired immunity during
HIV-1 infection.