Role of interleukin-18 in the development and pathogenesis of AIDS

Alexandre Iannello, Suzanne Samaranil, Olfa Debbeche, Cécile Tremblay, Emil Toma, Mohamed Rachid Boulasse, Jean Pierre Routy, Ali Ahmad

Research output: Contribution to journalReview article

23 Citations (Scopus)

Abstract

Interleukin-18 is a proinflammatory, proapoptotic, and proatherogenic cytokine belonging to the interleukin-1 family of cytokines. The cytokine exerts many unique immunologic and biological effects. It is produced as a biologically inactive and leaderless precursor protein, which must be cleaved into its mature form by caspase-1. The caspase-1 also exists in an inactive precursor in the cytosol and needs proteolytic auto-cleavage, which is catalyzed by the assembly of a multi-protein complex called inflammasome. Inside the circulation, interleukin-18 is bound to its naturally occurring antagonist called interleukin-18 binding 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 effects of the cytokine. Several researchers have reported that the concentrations and biological activities of the cytokine are increased in the circulation of HIV-infected patients. Unlike interleukin-18, the concentrations of its antagonist, interleukin-18 binding protein, are decreased in these persons. The cytokine may play a major role in the development and pathogenesis of AIDS in HIV-infected persons. Insufficient/lack of interleukin-12 and related cytokines may compromise the ability of interleukin-18 to induce interferongamma production from natural killer and T-cells. By inducing production of T-helper 2-type cytokines like interleukin-4, -5, -9, and -13 from basophils and mast cells, interleukin-18 promotes the development and differentiation of CD4+ naive T-cells into T-helper 2-type effector cells, which blunt anti-HIV immunity. The effect may be more pronounced in HIV-infected persons with compromised production of interleukin-12. Interleukin-18 also directly enhances viral replication. Because of its proapoptotic effects, the cytokine decreases survivability and promotes the death of various immune and nonimmune cells. It has also been documented to play a role in the depletion and wasting of subcutaneous fat from the limbs and face. The wasting is a characteristic feature of HIV-associated lipodystrophy. The cytokine is also likely to be involved in the higher incidence of atherosclerotic plaques and systemic insulin 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 an important role in the development and progression of the infection toward AIDS and associated clinical conditions. Therefore, its neutralization may represent an appropriate and useful immunotherapeutic strategy in these patients. It may delay AIDS progression and improve the immune status of infected persons. The best way to achieve this goal may be using exogenous interleukin-18 binding protein.

Original languageEnglish
Pages (from-to)115-125
Number of pages11
JournalAIDS Reviews
Volume11
Issue number3
Publication statusPublished - 2009

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Keywords

  • AIDS
  • Cytokines
  • HIV-1
  • HIV-associated dementia
  • IL-18
  • IL-18BP
  • Lipodystrophy

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Iannello, A., Samaranil, S., Debbeche, O., Tremblay, C., Toma, E., Boulasse, M. R., ... Ahmad, A. (2009). Role of interleukin-18 in the development and pathogenesis of AIDS. AIDS Reviews, 11(3), 115-125.