Systemic chronic immune activation is considered today as the driving force of CD4(+) T-cell depletion and acquired immunodeficiency syndrome (AIDS). A residual chronic immune activation persists even in HIV-infected patients in which viral replication is successfully inhibited by anti-retroviral therapy, with the extent of this residual immune activation being associated with CD4(+) T-cell loss. Unfortunately, the causal link between chronic immune activation and CD4(+) T-cell loss has not been formally established. This article provides first a brief historical overview on how the perception of the causative role of immune activation has changed over the years and lists the different kinds of immune activation characteristic of human immunodeficiency virus (HIV) infection. The mechanisms proposed to explain the chronic immune activation are multiple and are enumerated here, as well as the mechanisms proposed on how chronic immune activation could lead to AIDS. In addition, we summarize the lessons learned from natural hosts that know how to 'show AIDS the door', and discuss how these studies informed the design of novel immune modulatory interventions that are currently being tested. Finally, we review the current approaches aimed at targeting chronic immune activation and evoke future perspectives. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
