Role of Interleukin-18 in the Development and Pathogenesis of AIDS

Interleukin-18 is a proinflammatory, proapoptotic, and proatherogenic cytokine belonging to the interleukin-1family of cytokines. The cytokine exerts many unique immunologic and biological effects. It isproduced as a biologically inactive and leaderless precursor protein, which must be cleaved into itsmature form by caspase-1. The caspase-1 also exists in an inactive precursor in the cytosol and needsproteolytic auto-cleavage, which is catalyzed by the assembly of a multi-protein complex calledinflammasome.
Inside the circulation, interleukin-18 is bound to its naturally occurring antagonist called interleukin-18binding protein. The antagonist is induced as a negative feedback to increased interleukin-18 production.It protects body cells and tissues from the potentially destructive and harmful proinflammatory effectsof the cytokine.
Several researchers have reported that the concentrations and biological activities of the cytokine areincreased in the circulation of HIV-infected patients. Unlike interleukin-18, the concentrations of itsantagonist, interleukin-18 binding protein, are decreased in these persons. The cytokine may play amajor role in the development and pathogenesis of AIDS in HIV-infected persons. Insufficient/lack ofinterleukin-12 and related cytokines may compromise the ability of interleukin-18 to induce interferongammaproduction from natural killer and T-cells. By inducing production of T-helper 2-type cytokineslike interleukin-4, -5, -9, and -13 from basophils and mast cells, interleukin-18 promotes the developmentand differentiation of CD4+naive T-cells into T-helper 2-type effector cells, which blunt anti-HIVimmunity. The effect may be more pronounced in HIV-infected persons with compromised productionof interleukin-12. Interleukin-18 also directly enhances viral replication. Because of its proapoptoticeffects, the cytokine decreases survivability and promotes the death of various immune and nonimmunecells. It has also been documented to play a role in the depletion and wasting of subcutaneous fatfrom the limbs and face. The wasting is a characteristic feature of HIV-associated lipodystrophy. Thecytokine is also likely to be involved in the higher incidence of atherosclerotic plaques and systemicinsulin resistance in these patients.
Finally, increased production of the cytokine in the brain may lead to motor and cognitive dysfunctions,leading to the development of HIV-associated dementia.
In conclusion, increased interleukin-18 concentrations in HIV-infected persons are likely to play animportant role in the development and progression of the infection toward AIDS and associated clinical conditions. Therefore, its neutralization may represent an appropriate and useful immunotherapeuticstrategy in these patients. It may delay AIDS progression and improve the immune status of infectedpersons. The best way to achieve this goal may be using exogenous interleukin-18 binding protein.