Abstract
BackgroundWith the advent of antiretroviral therapy (ART) cases of immune reconstitution inflammatory syndrome (IRIS) have increasingly been reported. IRIS usually occurs in individuals with a rapidly rising CD4 T-cell count or percentage upon initiation of ART, who develop a deregulated immune response to infection with or without reactivation of opportunistic organisms. Here, we evaluated rises in absolute CD4 T-cells, and specific CD4 T-cell responses in 4 HIV-1+ individuals presenting with mycobacterial associated IRIS who received in conjunction with ART, IL-2 plus GM-CSF immunotherapy.MethodsWe assessed CD4 T-cell counts, HIV-1 RNA loads, phenotype for naïve and activation markers, and in vitro proliferative responses. Results were compared with those observed in 11 matched, successfully treated asymptomatic clinical progressors (CP) with no evidence of opportunistic infections, and uninfected controls.ResultsMedian CD4 T-cell counts in IRIS patients rose from 22 cells/μl before initiation of ART, to 70 cells/μl after 8 months of therapy (median 6.5 fold increase). This coincided with IRIS diagnosis, lower levels of naïve CD4 T-cells, increased expression of immune activation markers, and weak CD4 T-cell responses. In contrast, CP had a median CD4 T-cell counts of 76 cells/μl at baseline, which rose to 249 cells/μl 6 months post ART, when strong T-cell responses were seen in > 80% of patients. Higher levels of expression of immune activation markers were seen in IRIS patients compared to CP and UC (IRIS > CP > UC). Immunotherapy with IL-2 and GM-CSF paralleled clinical recovery.ConclusionThese data suggest that mycobacterial IRIS is associated with inadequate immune reconstitution rather than vigorous specific T-cell responses, and concomitant administration of IL-2 and GM-CSF immunotherapy with effective ART may correct/augment T-cell immunity in such setting resulting in clinical benefit.
Highlights
With the advent of antiretroviral therapy (ART) cases of immune reconstitution inflammatory syndrome (IRIS) have increasingly been reported
We investigated the quality and breadth of lymphoproliferative responses in a group of HIV-1+ patients on stable ART for > 6 months with suppressed viremia, diagnosed with Mycobacterium avium complex (MAC) associated IRIS, who were unresponsive to conventional anti-MAC therapy
Patients We studied both IRIS and clinical progressors (CP) patients who had been receiving effective ART for similar periods
Summary
With the advent of antiretroviral therapy (ART) cases of immune reconstitution inflammatory syndrome (IRIS) have increasingly been reported. It has been postulated that after treatment of late-stage HIV-1 infection, recovery and augmentation of immune function, and responses to previous sub-clinical infections with existing pathogens such as Mycobacterium spp, hepatitis B and hepatitis C viruses, or cytomegalovirus (CMV) may result in exacerbated inflammatory diseases [11,12,13,14,15,16,17,18,19] This phenomenon, described by others as immune reconstitution inflammatory syndrome (IRIS), is mostly seen in profoundly immunosuppressed patients with CD4 T-cell nadirs of less than 100 cells/μl, who upon receiving ART rapidly achieve an undetectable plasma viremia, and experience a very rapid increase in CD4 T cells [12,14]. This complex syndrome presents with either active opportunistic infections, or recurrence of previous infections
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