A high occurrence of inflammatory immune restoration is exclusively reported in patients who initiated antiretroviral therapy after the onset of severe immunodeficiency [1]. This disorder is reported as an immune reconstitution inflammatory syndrome (IRIS). Cryptococcosis-associated IRIS (C-IRIS) affects 20% of HIV-infected patients with cryptococcal meningitis (CM) after they commence antiretroviral therapy (ART).
We have recently identified transcriptomic biomarkers of dysregulated gene expression underlying non-fatal C-IRIS [2]. The goals of this study are to identify novel transcriptomic biomarkers of the development of C-IRIS and death due to C-IRIS.
In this study, we assessed peripheral blood gene expression in 4 groups of patients: [1] No C-IRIS or death; [2] C-IRIS survivors; [3] C-IRIS death; [4] Death but no C-IRIS (other causes). Cases of death or C-IRIS occurred within the first month of the ART. Total RNA was analyzed at: baseline (before ART initiation), at 2 and 4 (if survived) weeks on ART, and at the time of C-IRIS events. Next-generation sequencing reads were processed through the bioinformatic pipeline (Illumina) and the transcriptome was analyzed in JMP-Genomics and IPA statistical software.
Results: Principal component and decision tree-based algorithms distinguished transcriptomic biomarker signatures attributable to each group. In concordance with our previously published observations, low baseline expression of transcripts encoding interferon-inducible genes was significantly associated with C-IRIS events. Similarly, the upregulation of biomarker transcripts involved in innate immunity (inflammasome and toll-like receptor signaling), was observed at the time of the C-IRIS event in survivors’ group, and many of these same transcripts were upregulated to even higher levels in the C-IRIS-death group. In addition, the upregulation of transcripts encoding components of IL6, B-cell signaling, and Fc-gamma-receptor-mediated phagocytosis pathways were associated with death in those with C-IRIS.
Patients from the death but no C-IRIS group showed significant activation of NFkB and death receptor pathways at baseline. This group showed a strong signature of neutrophil activation/degranulation at 2 weeks on ART.
Conclusion: Low baseline expression of interferon-driven antiviral immune responses was predictive of the development of C-IRIS. Fatal C-IRIS events exhibited exaggerated inflammation due to the activation of both adaptive (B-cell) and innate immune cells.