Suppression of HIV replication by highly active antiretroviral therapy (HAART) often restores protective pathogen-specific immune responses, but in some patients the restored immune response is immunopathological and causes disease [immune restoration disease (IRD)]. Infections by mycobacteria, cryptococci, herpesviruses, hepatitis B and C virus, and JC virus are the most common pathogens associated with infectious IRD. Sarcoid IRD and autoimmune IRD occur less commonly. Infectious IRD presenting during the first 3 months of therapy appears to reflect an immune response against an active (often quiescent) infection by opportunistic pathogens whereas late IRD may result from an immune response against the antigens of non-viable pathogens. Data on the immunopathogenesis of IRD is limited but it suggests that immunopathogenic mechanisms are determined by the pathogen. For example, mycobacterial IRD is associated with delayed-type hypersensitivity responses to mycobacterial antigens whereas there is evidence of a CD8 T-cell response in herpesvirus IRD. Furthermore, the association of different cytokine gene polymorphisms with mycobacterial or herpesvirus IRD provides evidence of different pathogenic mechanisms as well as indicating a genetic susceptibility to IRD. Differentiation of IRD from an opportunistic infection is important because IRD indicates a successful, albeit undesirable, effect of HAART. It is also important to differentiate IRD from drug toxicity to avoid unnecessary cessation of HAART. The management of IRD often requires the use of anti-microbial and/or anti-inflammatory therapy. Investigation of strategies to prevent IRD is a priority, particularly in developing countries, and requires the development of risk assessment methods and diagnostic criteria.

BackgroundTo determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-speci®c immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log 10 copies/mL). MethodsBaseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients. ResultsThirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the ®rst 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria-and HCV-related diseases were associated with restoration of pathogen-speci®c immune responses. ConclusionsWe conclude that improved immune function in immunode®cient patients treated with HAART may restore pathogen-speci®c immune responses and cause in¯ammation in tissues infected by those pathogens. Key words: HAART, HIV, immune restorationReceived: 4 June 1999, accepted 13 September 1999 IntroductionWhile the immediate aim of using antiretroviral therapy is suppression of HIV replication, the ultimate aim is restoration or maintenance of protective HIV-speci®c and pathogen-speci®c immune responses. Treatment of immunode®cient patients with highly active antiretroviral therapy (HAART) appears to restore pathogen-speci®c immune responses resulting in prevention or regression of diseases caused by opportunistic pathogens [1]. However, in some patients suppression of HIV replication by antiretroviral therapy and the resultant increase in blood CD4 T-cells is associated with in¯ammation in tissues infected by those pathogens. Thus, disease related to subclinical or pre-existent infections by Mycobacterium avium complex (MAC) [2±4], M. tuberculosis (MTB) [5,6], Bacille Calmette±Guerin (BCG) [7], cytomegalovirus (CMV) [8±10], hepatitis B virus (HBV) [11,12], hepatitis C virus (HCV) [13] immunological response to HAART. Many of these disease episodes were associated with the presence of a pathogenspeci®c immune response and/or more exaggerated inammatory response than is usually present in patients with opportunistic infections. It has therefore been argued that the disease results from the effects of a restored immune response against the pathogen [2±7,10,11,13,14]. However, Michelet et al. have argued that`opportunistic infections' in patients treated...

We previously demonstrated that NK cells from HIV-infected individuals have elevated expression of activation markers, spontaneously degranulate ex vivo, and decrease expression of a signal-transducing protein for NK-activating receptors, FcRγ. Importantly, these changes were maintained in virologically suppressed (VS) individuals receiving combination antiretroviral therapy (cART). In this study, we show that loss of FcRγ is caused by the expansion of a novel subset of FcRγ−CD56dim NK cells with an altered activation receptor repertoire and biological properties. In a cross-sectional study, FcRγ− NK cells as a proportion of total CD56dim NK cells increased in cART-naive viremic HIV-infected individuals (median [interquartile range] = 25.9 [12.6–56.1] compared with 3.80 [1.15–11.5] for HIV− controls, p &lt; 0.0001) and in VS HIV-infected individuals (22.7 [13.1–56.2] compared with 3.80 [1.15–11.5], p = 0.0004), with no difference between cART-naive and VS patients (p = 0.93). FcRγ− NK cells expressed no NKp30 or NKp46. They showed greater Ab-dependent cellular cytotoxicity activity against rituximab-opsonized Raji cells and in a whole-blood assay measuring NK responses to overlapping HIV peptides, despite having reduced CD16 expression compared with conventional NK cells. Their prevalence correlated with CMV Ab titers in HIV− subjects but not in HIV+ individuals, and with the inflammatory marker CXCL10 in both groups. The expansion of a subset of NK cells that lacks NKp30 and NKp46 to ∼90% of CD56dim NK cells in some VS HIV+ individuals may influence NK-mediated immunosurveillance in patients receiving cART.

Patients with a history of IRD after HAART have elevated levels of IL-6 and sIL-6R.