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IL-33/ST2 Axis as an Inflammatory and Gut Damage Marker in Primary HIV Infection
Vikram Mehraj1; Mohammad-Ali Jenabian2; Wei Cao1; Rosalie Ponte3; Bertrand Lebouché4; Réjean Thomas5; Jean-Guy Baril6; Roger LeBlanc7; Cécile Tremblay8; Jean-Pierre Routy1
1Rsr Inst of the McGill Univ Hlth Cntr, Montreal, QC, Canada;2Univ du Québec à Montréal, Montreal, QC, Canada;3Rsr Inst of the McGill Univ Hlth Cntr, Montréal, QC, Canada;4McGill Univ Hlth Cntr, Montreal, QC, Canada;5Clinique Médicale l'Actuel, Montreal, QC, Canada;6Clinique Médicale Quartier Latin, Montreal, QC, Canada;7Clinique Médicale OPUS, Montreal, QC, Canada;8CRCHUM, Montreal, QC, Canada
The alarmin IL-33 and its receptor ST2 mainly expressed by innate lymphoid type 2 cells are involved in microbial invasion, cytokine induction and promotion of cytotoxic CD8 T cells. The soluble ST2 (sST2) binds IL-33 as a decoy receptor to negate its inflammatory/healing effects. sST2 has been validated as a prognostic marker in cardiac insufficiency, IBD, GVHD and been evaluated in HIV. We assessed relationship of IL-33/ST2 axis with gut mucosal damage markers in patients undergoing primary HIV infection (PHI).
A total of 41 patients diagnosed during PHI were followed: 24 remained untreated while 17 initiated early ART. We also assessed chronically infected patients treated (n=15) or not (n=14), elite controllers (EC, n=10) and uninfected controls (n=15). IL-33 and sST2 plasma levels were compared with markers of gut epithelial damage (I-FABP), microbial translocation (LPS, sCD14) and TNF-α, IL-7 and IDO immunosuppressive activity (Kynurenine/Tryptophan). CD4 and CD8 T-cell activation (HLADR/CD38) and exhaustion (PD-1) and Tregs were assessed by FACS.
sST2 levels were elevated during primary (18.6 ng/mL, p<0.001) and chronic (15.6 ng/mL, p=0.034) HIV infection as compared to EC and controls (10.5 and 11.2 ng/mL). IL-33 levels were close to limit of detection in all groups and controls. sST2 levels positively correlated with plasma IDO activity (r=0.1981, p=0.021), TNF-α (r=0.3051, p=0.002) and IL-7 (r=0.2269, p=0.006), CD8 count (r=0.2721, p=0.001) and inversely correlated with CD4/CD8 ratio (r=-0.2195, p=0.015). However, no association of sST2 was observed with CD4 count, Treg and viral load (p>0.05). sST2 was associated with expression of activation and exhaustion markers on CD4 & CD8 T cells (p<0.05) and correlated with I-FABP (r=0.2099, p=0.039), LPS (r=0.1865, p=0.042) and sCD14 (r=0.2188, p=0.037). Prospective analysis following PHI showed that early ART had no impact on sST2 and gut damage markers contrasting with normalization of IDO, inflammatory cytokines and activation/exhaustion markers.
sST2 was elevated in primary and chronic HIV infection correlating with elevation of CD8 T cells and their expression of activation/exhaustion markers. Similar to other gut damage markers, sST2 never improved following early ART, contrasting with reversal of immune activation/exhaustion markers, IDO and inflammatory cytokines. By linking immune function, and tissue damage, IL-33/ST2 axis may induce gut injury and represents an immunotherapeutic target.