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Title: NK cell and T-cell immunity and TLR responsiveness during chronic HIV-1 infection
Author: Coleman, Adam Robert
ISNI:       0000 0004 2728 7806
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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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.
Supervisor: Goodier, Martin ; Imami, Nesrina Sponsor: European Union
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral