Microbiology & Immunology - Theses
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ItemNatural killer cell-mediated antibody dependent cellular cytotoxicity against HIV( 2010)Natural Killer (NK) cell-mediated antibody dependent cellular cytotoxicity (ADCC) is a potentially important immune mechanism against virus-infected cells. The protective ability of ADCC has been largely overlooked in as a beneficial immune response against HIV. In order to assess the importance of ADCC, we recruited a cohort of 79 Antiretroviral therapy naïve HIV-infected subjects. Within this cohort ADCC responses were characterised annually using a novel ADCC ICS assay. We observed ADCC responses within 84% (66 of 79) of the cohort. Env was the most common ADCC target, however ADCC activity was observed to all of the HIV proteins, including the intracellular proteins Pol and all the accessory proteins. We observed a highly significant correlation (p<0.004) between gp140-specific ADCC responses and delayed disease progression, when testing autologous plasma on healthy donor cells. Surprisingly NK cell-mediate ADCC IFNγ cytokine secretion correlated more significantly than ADCC cytotoxicity. The ADCC ICS assay has the ability to map ADCC epitopes since overlapping peptide pools can be used as test antigens. Using this assay, we identified 56 linear ADCC epitopes within Env and 3 novel ADCC epitopes to Vpu. 9 of the Env epitopes were shared by 2 or more subjects and may become potential vaccine targets. We hypothesised that if ADCC was an important immune response, it would exert significant immune pressure upon the virus, causing immune escape. Mutational escape from ADCC responses was detected in 57% of epitopes that were tested against the subjects’ autologous virus sequence peptide. Stored plasma sequences from earlier time points of infection in subjects had sequences identical or more similar to consensus sequence. ADCC responses initially generated by autologous virus sequences early in infection were commonly completely unable to recognise concurrent virus sequence. Gp140 proteins containing ADCC escape mutations resulted in poorer ADCC activity, confirming virus escape. Multiple other studies were conducted to elucidate the importance of ADCC activity. We observed that activation of autologous NK cells in response to peptide stimulation by ADCC antibodies appears to occur at least as rapidly as activation of Gag-specific CTLs, suggesting that ADCC may be potentially as effective as CTL in preventing the release of new virions from HIV-infected cells. Distinctly different profiles of ADCC killing kinetics were observed within LTNP subjects in comparison to other faster progressing subjects. Statistically significant differences in ADCC activity to recombinant gp140 antigen stimulation were also observed between LTNP subjects who maintained healthy prognosis, in comparison to subjects that eventually progressed onto ART. This work suggests that ADCC responses may be associated with LTNP disease progression. This thesis highlights the complexity of NK cell-mediated ADCC activity in HIV infection and predicts that ADCC could be a valuable immune response to be induced by HIV vaccines and opens new avenues towards the study and development of ADCC-based HIV vaccines.