IL-18 is a pleiotropic and multifunctional cytokine that belongs to the IL-1 
family. It is produced as a biologically inactive precursor, which is cleaved 
into its active mature form mainly by caspase-1. The caspase becomes active from 
its inactive precursor (procaspase-1) upon assembly of an inflammasome. Because 
of IL-18's potential pro-inflammatory and tissue destructive effects, its 
biological activities are tightly controlled in the body by its naturally 
occurring antagonist called IL-18BP. The antagonist is produced in the body both 
constitutively and in response to an increased production of IL-18 as a negative 
feedback mechanism. Under physiological conditions, most of IL-18 in the 
circulation is bound with IL-18BP and is inactive. However, an imbalance in the 
production of IL-18 and its antagonist (an increase in the production of IL-18 
with a decrease, no increase or an insufficient increase in the production of 
IL-18BP) has been described in many chronic inflammatory diseases in humans. The 
imbalance results in an increase in the concentrations of free IL-18 (unbound 
with its antagonist) resulting in increased biological activities of the 
cytokine that contribute towards pathogenesis of the disease. In this article, 
we provide an overview of the current biology of IL-18 and its antagonist, 
discuss how the imbalance occurs in HIV infections and how it contributes 
towards development of AIDS and other non-AIDS-associated clinical conditions 
occurring in HIV-infected individuals undergoing combination anti-retroviral 
therapy (cART). Finally, we discuss challenges facing immunotherapeutic 
strategies aimed at restoring balance between IL-18 and its antagonist in these 
patients.