1. Immune Reconstitution Inflammatory Syndrome (IRIS)

2. Clinical Diagnosis/Features IRIS is a well recognized (but unknown MOA) condition seen in AIDS or other immunosuppressed conditions resulting in an overwhelming response to antigen as the immune system begins to recover IRIS is a well recognized (but unknown MOA) condition seen in AIDS or other immunosuppressed conditions resulting in an overwhelming response to antigen as the immune system begins to recover Most commonly occurs with TB, M. avium, Cryptococcus, CMV, VZV, EBV, and viral hepatitis Most commonly occurs with TB, M. avium, Cryptococcus, CMV, VZV, EBV, and viral hepatitis Up to 50% of patients with past history of treated cryptococcus are at risk of developing IRIS after initiation of ART Up to 50% of patients with past history of treated cryptococcus are at risk of developing IRIS after initiation of ART Risk factors for cryptococcal IRIS include low initial CD4 Risk factors for cryptococcal IRIS include low initial CD4 HIV infection revealed by cryptococcal infection HIV infection revealed by cryptococcal infection Fungemia Fungemia Rise in absolute CD4 count not recognized as a risk factor Rise in absolute CD4 count not recognized as a risk factor

3. Clinical Diagnosis/Features Two types, early vs. late IRIS Two types, early vs. late IRIS Early type seen within the first few months of ART representing response to occult infection Early type seen within the first few months of ART representing response to occult infection Characterized by subclinical opportunistic infection Characterized by subclinical opportunistic infection Unmasked by ART Unmasked by ART Infectious/active pathogens are present on cultures Infectious/active pathogens are present on cultures Late “paradoxical” type reaction seen in up to 3 years Occurs after successful past treatment Late “paradoxical” type reaction seen in up to 3 years Occurs after successful past treatment Symptomatic relapse after successful past treatment Symptomatic relapse after successful past treatment Antigen driven immune activation Antigen driven immune activation Sterile cultures Sterile cultures Either form can be related to serious morbidity and mortality if not addressed and treated Either form can be related to serious morbidity and mortality if not addressed and treated Note that IRIS should not represent failure to ART, quite the contrary, can be a marker of successful response to ART Note that IRIS should not represent failure to ART, quite the contrary, can be a marker of successful response to ART

4. Immunopathogenesis Maintenance of immune homeostasis is partially regulated by CD4+CD25+ T- regulatory cells (T-regs) Maintenance of immune homeostasis is partially regulated by CD4+CD25+ T- regulatory cells (T-regs)

5. Immunopathogenesis Immune dysregulation in IRIS may occur from: Immune dysregulation in IRIS may occur from: Absence of functional T- regs Absence of functional T- regs Lack of proper costimulation (CTLA-4) to self limit immune responses Lack of proper costimulation (CTLA-4) to self limit immune responses Biased cytokine profiles from a limited pool of adaptive immune cells (anti-inflammatory vs. inflammatory cytokine balance) Biased cytokine profiles from a limited pool of adaptive immune cells (anti-inflammatory vs. inflammatory cytokine balance)

6. Treatment Overall goal is to reduce antigenic burden and address immunologic response Overall goal is to reduce antigenic burden and address immunologic response Empiric treatment for inciting antigen is presently recommended and directed at pathogen of interest Empiric treatment for inciting antigen is presently recommended and directed at pathogen of interest Some studies argue for treatment of aberrant immune response with corticosteroids Some studies argue for treatment of aberrant immune response with corticosteroids No studies yet to address use of other anti- inflammatory methods such as immunomodulation or use of biologics No studies yet to address use of other anti- inflammatory methods such as immunomodulation or use of biologics

7. References French, M. Immune reconstitution inflammatory syndrome: A reappraisal. Clinical Infectious Diseases. 2009; 48:101-7 French, M. Immune reconstitution inflammatory syndrome: A reappraisal. Clinical Infectious Diseases. 2009; 48:101-7 Bonham, S., et al. Biomarkers of HIV immune reconstitution inflammatory syndrome. Biomark Med. 2008; 2(4):349-361 Bonham, S., et al. Biomarkers of HIV immune reconstitution inflammatory syndrome. Biomark Med. 2008; 2(4):349-361 Sungkanuparph, S., et al. Timing of Cryptococcal immune reconstitution inflammatory syndrome after anti-retroviral therapy in patients with AIDS and cryptococcal meningitis. Acquired Immune Deficiency Syndrome. 2007; 45:595-6 Sungkanuparph, S., et al. Timing of Cryptococcal immune reconstitution inflammatory syndrome after anti-retroviral therapy in patients with AIDS and cryptococcal meningitis. Acquired Immune Deficiency Syndrome. 2007; 45:595-6 Salicru’s images Salicru’s images