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Abstract
The theme of this thesis is an exploration of some of the physiological aspects, both positive and negative of two host-directed therapies, recombinant interleukin-2 (rIL-2) and small molecule blockers of the chemokine-receptor-5 (CCR5). The cytokine, IL-2, an immunomodulating agent, has been the subject of more than two decades of research culminating in the negative results of the Phase III clinical endpoint studies. The CCR5-receptor antagonists have been a focus of research for 15 years, following the recognition of the CCR5-receptor as critical for human immunodeficiency virus (HIV) virus entry into CD4+ T-cells (and other immune cells). As this class of anti-HIV agent blocks a host receptor there is the potential to impact on normal physiology by so doing.
The introductory Chapter presents a review of the recombinant interleukin-2 and small molecule blockers of CCR5 as HIV therapeutic agents. Next, two physiological aspects of rIL-2 therapy in the setting of the Phase III study, Evaluation of Subcutaneous Proleukin in an International Trial (ESPRIT) study are presented. First, an exploration of CD4+ T-cell change and clinical events (i.e. Progression of Disease events (AIDS)/death, all cause mortality and Serious Non-AIDS events (SNA)) in ESPRIT participants receiving a protease inhibitor (PI) based regimen vs. a non-nucleoside reverse transcriptase (NNRTI) based regimen and whether any interaction between PI and rIL-2 existed. Next, the incidence of first episode bacterial pneumonia, the most commonly reported infection reported in ESPRIT, was explored in order to better understand the temporal relationship between the inflammatory surge induced by rIL-2 and risk of bacterial pneumonia.
In the second half of the thesis, data on the safety, efficacy and pharmacokinetic profile of a novel CCR5-receptor blocker, SCH532706 is presented. Having established an antiviral effect of this agent, the immunological changes in cells expressing CCCR5 (T-cell subsets and plasmacytoid dendritic cells) and the changes in antigen-specific cells during sequential exposure of the same group of patients to monotherapy with the CCR5-receptor blocker, a no therapy period and combination antiretroviral therapy (cART) was explored.