Background: Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) affects ~20% of HIV-infected patients with cryptococcal meningitis (CM) after they commence antiretroviral therapy (ART). The goal of this study is to identify novel transcriptomic biomarkers of fatal C-IRIS (within COAT trial).
Results: We assessed peripheral blood gene expression in 4 cohorts of patients:  No C-IRIS or Death (control);  C-IRIS survivors;  Fatal C-IRIS;  Death without C-IRIS (other causes). Total RNA was analyzed at weeks 0,1,4,8 (if survived) on ART, and at the time of C-IRIS events. Next-generation sequencing reads were processed through the bioinformatic pipeline and the whole transcriptome was analyzed in JMP15pro and IPA statistical modeling software. Baseline gene expression in the fatal C-IRIS group exhibited significant activation of the interferon response pathway, and upregulation of transcripts encoding components of IL1,6,8, and other acute-phase response molecules when compared to three other groups. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within neutrophil activation pathways, including fMLP, Rho family GTPases, HMGB1 were upregulated. The Partial Least Squares model estimated above mentioned pathways as predictors of fatal outcome.
Conclusion: The overactivated innate immunity, involving Toll-like receptor/inflammasome, and neutrophil-induced oxidative stress pathways predict fatal C-IRIS. The results of this study provide insight into molecular drivers of fatal C-IRIS to inform future diagnostic tests development or guide targeted treatments.
Keywords: AIDS/HIV, Cryptococcosis-associated Immune reconstitution inflammatory syndrome (C-IRIS), antiretroviral therapy.
Abbreviations: IL: Interleukins; fMLP pathway: N-formyl-Met-Leu-Phe or N-Formylmethionyl-leucyl-phenylalanine; Rho Family GTPases: Ras homologous family guanosine triphosphatases; HMGB1: High Mobility Group Box-1.