An IRIS is an undesirable outcome of restoring immune responses against an active (sometimes unrecognised) HIV-related infection or antigens of non-viable pathogens remaining after treatment of the infection (7). The strongest risk factors for an IRIS are a low CD4⁺ T cell count (usually <50/mL) and a high pathogen load (3, 7, 13) The latter is a consequence of decreased pathogen-specific immune responses associated with severe CD4⁺ T cell deficiency as well as depletion and/or dysfunction of other immune cells, which include B cells in the case of C-IRIS (14). The disease-causing inflammatory response in an IRIS is largely determined by the provoking pathogen (3) with mycobacterial and fungal IRIS being associated with granulomatous and/or suppurative inflammation, while tissue inflammation in an IRIS associated with infections by viruses, such as herpes simplex virus (HSV) or JC virus, is usually characterised by CD8⁺ T-cell infiltration.

The majority of IRIS research has been undertaken on mycobacterial and cryptococcal IRIS. TB-IRIS and MAC-IRIS are associated with an increase in the frequency of pathogen-specific CD4⁺ T cells producing multiple cytokines (interferon-gamma, tumour necrosis factor and interleukin-2) and with cytotoxic activity (15, 16) whereas an increase in pathogen-specific T cell responses has not been demonstrated in C-IRIS (17), though the latter was examined using whole blood interferon gamma release assays. There is also convincing evidence that activation of monocytes and neutrophils contributes to the immunopathology of TB-IRIS, particularly through activation of monocyte inflammasome pathways (18-20), MAC-IRIS (16), and C-IRIS (22, 23). It therefore appears that an IRIS associated with mycobacterial and cryptococcal infections reflects the restoration of diverse cellular immune responses with pro-inflammatory activity against pathogens, which generates an exaggerated inflammatory response. Further information about the immunopathogenesis of the various types of IRIS is provided elsewhere (24, 25).