CROI 2016 Abstract eBook

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Poster Abstracts

Methods: 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. Results: 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. Conclusions: 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. 238 Probiotics Module Th1/Th17 and IFN Response in HIV Patients on Suppressive cART Ivan Schietroma 1 ; Noemi Giustini 1 ; Sara Serafino 1 ; Gabriella De Girolamo 1 ; Mauro Andreotti 2 ; Carolina Scagnolari 1 ; Giancarlo Ceccarelli 1 ; Gabriella D’Ettorre 1 ;VincenzoVullo 1 ; for the Carla Selvaggi, Giuseppe Corano, Andrea Mastrangelo, Gianfranco Fanello, Fausto Fiocca, Marileda Indinnimeo 1 Sapienza Univ of Rome, Rome, Italy; 2 InstSuperiore di Sanità, Rome, Italy

Background: The gut-associated lymphoid tissue (GALT) is an important site of HIV replication and immune dysfunction; previous works have demonstrated the failure of antiretroviral therapy (ART) in controlling the immune activation and modifying the balance of immune cells profiling in intestinal mucosa; we evaluated the immunomodulatory effect of six-month of probiotics supplementation in ART experienced subjects. Methods: Ten ART treated HIV-infected subjects underwent endoscopic procedures and blood collection prior to initiation of probiotics supplementation (T0) and after 6 months (T6) (Trial #NCT02276326). Normal mucosa biopsies were obtained from five different intestinal sites; lamina propria lymphocytes (LPLs) were isolated. Cell phenotype (CD3, CD4, CD45Ro, CD27) and activation markers (CD38 and HLA-DR) were detected on freshly samples. Th1 and Th17 cell phenotype were detected by IL-17A and IFNγ intra-citoplasmatic staining, respectively, after overnight PMA and ionomycine activation. IFNα subtypes (n=12), IFNβ, IFNR1, IFNγ mRNAs were quantified by RT-PCR. Data were analyzed by Wilcoxon signed-ranked test (paired data) and Spearman’s correlation using SPSS v22. Results: Subjects assumed 1.8x10 12 live bacteria daily for 6 months; no adverse event was observed during the follow-up. All subjects had undetectable plasmatic viral load at T0 and T6. The median CD4 cell number at T0 was 674 cells/mm 3 and didn’t change at T6. Intestinal and blood Th17 and Th1 frequencies at T6 were increased in CD4 population and in EM (Effector Memory) and CM (Central Memory) subpopulations (Tab 1). A reduction of CD38 and HLA-DR was observed at T6 in CD4 and in all

EM and CM subpopulations. The most statistically significant increase in Th17 frequencies in gut was observed in CM population and this level at T6 was inversely correlated to the percentages of CD4 cells expressing HLA-DR in EM subpopulation (r=-0.79 p=0.006). A decrease in IFNγ expression and an increase in IFNα subtypes (10,14,17 and 21) expression were recorded at T6 in gut whereas no such differences were observed for the other IFN genes analyzed in gut and peripheral blood compartments. Conclusions: Probiotics supplementation for 6 months in HIV+ individuals on effective ART induced a marked recovery in the levels of both Th17 and Th1 cells in GALT and in peripheral blood and a significant reduction of cellular markers of activation. Furthermore, the use of probiotics was associated with a specific modulation of IFN-mediated immunity in the gut. 239 Cenicriviroc Decreases sCD14 and LBP Levels Without Affecting Gut Permeability Background: Cenicriviroc (CVC), a potent oral, once-daily CCR2/CCR5 antagonist, blocks HIV entry through CCR5 blockade and inhibits monocyte trafficking through CCR2. Monocyte recruitment promotes atherosclerosis, hepatic fibrosis and other end-organ diseases in HIV infection. In a completed randomized, double-blind study of 48 weeks of CVC or efavirenz (EFV) with tenofovir/emtricitabine (TDF/FTC) (Study 652-2-202; NCT01338883), levels of sCD14, a marker of monocyte activation, significantly decreased with CVC treatment independent of HIV-1 RNA changes but increased in the EFV arm. We aimed to determine whether decreases in this monocyte activation marker with CVC were attributable to decreased intestinal permeability and microbial translocation. Methods: 135 men and 8 women were enrolled, age 35±11 years (46 Black, 35 Hispanic, 53 White, 9 Other). Intestinal fatty acid binding protein (I-FABP), zonulin, flagellin and lipopolysaccharide binding protein (LBP) were measured by ELISA on stored plasma. As sCD14 levels decreased in participants who received TDF/FTC with CVC either 100mg or 200mg (N=115), these arms were pooled and compared to the armwho received TDF/FTC with EFV 600mg (N=28). Median values were compared between groups by Mann- Whitney test and longitudinal within-group comparisons by Wilcoxon matched-pairs signed rank test. Pearson correlation coefficients were calculated. Results: Plasma I-FABP and flagellin levels increased in both CVC and EFV groups whereas LBP levels decreased in both groups during 48 weeks of ART (see table). Zonulin levels did not change significantly. Lower LBP levels were associated with lower CRP levels in both groups at most time points and with lower GGT at weeks 24 and 48 in CVC group. In the CVC group, lower sCD14 levels were associated with lower LBP levels at weeks 0 and 12 and lower I-FABP levels at weeks 12 and 24. Lower sCD14 levels were associated with lower LDL cholesterol levels at all time points. Conclusions: The decrease in sCD14 levels reflecting a reduction in monocyte activation with CVC was not accompanied by decreased intestinal permeability (I-FABP, zonulin) or bacterial products (flagellin). The decrease in LBP with CVC could reflect decreased LPS in the liver, but the consistent correlation with decreases in CRP suggests decreased activation of the acute phase response. Thus, CVC decreases sCD14 levels independently of changes in microbial translocation, viremia or gut integrity, suggesting CVC may directly inhibit monocyte activation. Netanya S. Utay 1 ; Anoma Somasunderam 1 ; Maitreyee Nigalye 1 ;Will Chang 2 ; Star Seyedkazemi 2 ; Eric Lefebvre 2 1 Univ of Texas Med Branch at Galveston, Galveston, TX, USA; 2 Tobira Therapeutics, Inc, San Francisco, CA, USA

Poster Abstracts

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CROI 2016