Abstract
Chronic HIV infection is characterised by a generalised hyperactivation of the immune system, which drives disease progression towards AIDS and increases the risk of non-AIDS morbidity such as cardiovascular disease. This immune hyperactivation persists to some degree despite antiretroviral therapy, and may contribute to impaired regeneration of the immune system in a subset of treated patients.
The aim of this thesis was to further explore the implications of HIV-associated immune activation on immune function. To his end, three studies were performed.
The first study analysed plasma markers of inflammation in 112 patients initiating antiretroviral therapy, and identified elevated plasma levels of the chemokine MIP-1β as a putative biomarker predictive of poor CD4 gain, or so-called immunological non-response. Elevated MIP-1β may represent a facet of HIV-associated immunopathology contributing to immunological non-response.
The second study explored an in vitro assay to quantify the effect of inhibitory signalling molecules IL-10, TGF-β, PD-1 and CD160 on HIV peptide-induced CD8+ T cell proliferation. These signalling pathways attenuated HIV-specific T cell function with a high degree of inter-individual variability. An assay such as this may be of use in predicting response to immunotherapies targeting these pathways.
The third and final study was an exploratory clinical trial to determine the immunomodulatory effects of cyclooxygenase 2 inhibitor etoricoxib in HIV-infected patients. Etoricoxib reduced immune activation and coagulation parameters in antiretroviral therapy-naïve HIV-infected patients, but this effect was modest and may not be sufficient to improve clinical endpoints. Etoricoxib had no appreciable effect in patients on stable antiretroviral therapy. These results indicate a limited role for cyclooxygenase inhibitors as immunotherapeutic adjuvant agents in HIV-infected patients.