CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

distinguished between the other profiles by a signature of 8 biomarkers. Only one of these immune profiles was significantly associated with marks of metabolic syndrome: hypertriglyceridemia (OR 4.18 [95% CI 1.08-16.19], p = 0.038), hyperinsulinemia (OR 12.17 [95% CI 1.79-82.86], p = 0.011), and lipodystrophy (OR 4.87 [95% CI 1.36-17.39], p = 0.015). Conclusions: We have uncovered an immune signature that might be useful for the prevention and early diagnosis of metabolic syndrome in HIV-infected patients. A better knowledge of the links between immune activation profiles and their consequences might highlight biomarkers predictive of comorbidities, as well as new therapeutic targets in HIV-induced immune activation or other situations of chronic hyperactivity of the immune system including aging. 277 Immune Activation, Cell Turnover, and Exhaustion in HIV+WomenWith Heavy Alcohol Use Seema N. Desai 1 ; KathleenWeber 2 ; Jane Burke-Miller 3 ; Audrey L. French 4 ; Marion Peters 5 ; Mark H. Kuniholm 6 ; Elizabeth Golub 7 ; Kendall J. Bryant 8 ; Alan L. Landay 9 ; Mardge Cohen 10 1 Rush Univ Med Cntr, Chicago, IL, USA; 2 CORE Cntr/Cook County Hlth and Hosp System and Hektoen Inst of Med, Chicago, IL, USA; 3 Hektoen Inst of Med, Chicago, IL, USA; 4 CORE Cntr/John H. Stroger Jr Hosp of Cook County, Chicago, IL, USA; 5 Univ of California San Francisco, San Francisco, CA, USA; 6 Albert Einstein Coll of Med, Bronx, NY, USA; 7 Johns Hopkins Bloomberg Sch of PH, Baltimore, MD, USA; 8 Natl Inst on Alcohol Abuse and Alcoholism, Bethesda, MD, USA; 9 Rush Univ, Chicago, IL, USA; 10 John H. Stroger Jr. Hosp of Cook County and Rush Med Coll, Chicago, IL, USA Background: Heavy alcohol use in HIV disease is associated with accelerated HIV disease progression. Immune activation is a hallmark of HIV disease. Chronic T cell activation results in proliferation/cell turnover and immune exhaustion. We hypothesize that chronic heavy drinking through biological pathways of immune activation will contribute to immunosuppression and HIV disease progression. Methods: Women’s Interagency HIV Study (WIHS) hepatitis C seronegative participants were categorized in 4 groups of HIV+ and HIV- individuals with chronic heavy alcohol consumption (> 7 drinks/week) and abstainers, matched on age, race, education and history of IDU, n=25/group. Markers of immune activation (HLADR+CD38+), cell turnover (Ki67+), and immune exhaustion (PD-1+) were measured on CD4 and CD8 T cells using 10 color flow-cytometry at 4 time points from 2001-11. We tested baseline group differences (ANOVA/t-test); changes in markers over time (random regression models); and relationships of markers with log10 viral load (partial correlations). Results: The mean % of CD8 HLADR+CD38+ cells in HIV+ chronic drinkers was significantly higher than among HIV+ abstainers at baseline (p=0.02); this difference increased significantly over time (β=3.39, p=0.03). The mean % of CD8 Ki67+ cells in HIV+ chronic drinkers was also significantly higher than among HIV+ abstainers at baseline (p=0.02), and over time (β=1.49, p<0.01).The mean % of CD8 PD1+ cells was higher in HIV+ chronic drinkers than HIV+ abstainers at baseline (p=0.05); but did not significantly increase over time. In contrast, % CD4 HLADR+CD38+, CD4 Ki67+, and CD4PD-1+ cells in HIV+ chronic drinkers did not differ at baseline compared to HIV+ abstainers but did increase significantly over time (β=0.67, p=0.01), (β=0.81, p=0.01), (β=3.82, p<0.01), respectively. Adjusting for time and HAART adherence, % immune activation (CD4 & CD8 HLADR+CD38+) correlated positively (p<0.05) with viral load in HIV+ drinkers but not in abstainers. There were no significant differences in either CD8 or CD4 T-cell markers among HIV- women by drinking status at baseline or over time. Conclusions: CD8 T cell activation, cell turnover, and exhaustion, were associated with chronic heavy drinking in HIV+ women. Chronic heavy drinking in HIV+ women was also associated with increases in activated and cycling CD4 T cells which has implication to HIV replication. Thus, alcohol related immune dysregulation could contribute to accelerated HIV disease progression. 278 Oral Bovine Immunoglobulin Reduces Immune Activation in HIV+ Immune Nonresponders David Asmuth 1 ; Netanya S. Utay 2 ; Ma Somsouk 3 ; Zhong M. Ma 4 ; PeterW. Hunt 3 ; Surinder K. Mann 1 ; Bryon M. Petschow 5 ; Audrey L. Shaw 5 ; Christopher J. Detzel 5 ; Eric M.Weaver 5 1 Univ of California Davis Med Cntr, Sacramento, CA, USA; 2 Univ of Texas Med Branch at Galveston, Galveston, TX, USA; 3 Univ of California San Francisco, San Francisco, CA, USA; 4 Cntr for Comparative Med, Univ of Califlornia Davis, Davis, CA, USA; 5 Entera Hlth, Inc, Cary, NC, USA Background: A multi-center trial in patients (pts) with HIV-enteropathy showed that oral administration of serum-derived bovine immunoglobulin/ protein isolate (SBI) led to increases in peripheral and mucosal CD4+ T-cells after 4 and 24 weeks among pts in the baseline (BL) CD4 lowest quartile (LQ; ≤418 cells/mL). Here we report on analyses of immune activation and gastrointestinal (GI) biomarkers in plasma samples in LQ pts that provides insight into the restoration of peripheral and mucosal immunity seen in previous SBI studies. Methods: A total of 103 HIV+ pts receiving suppressive ART (median 19 cp/mL and 8.3 years, respectively) and a history of HIV enteropathy were enrolled. Median CD4 T-cell counts were 637 cells/mL (189-1754). Pts were randomized to receive blinded SBI 2.5 vs 5.0 grams (g) BID or placebo during a 4-week lead-in phase followed by SBI 2.5 vs 5.0 g BID for 20 weeks. Earlier analysis showed no change among all study pts but significant increases in median peripheral CD4 counts from BL to week 24 (311 to 366 cells/mL, p=0.002) in pts in the LQ at BL. Additionally, a separate duodenal biopsy sub-study at week 0 and 24 was performed in 8 pts with duodenal CD4 densities increasing from 217 to 329 cells/mm 2 (p=0.02). Therefore, plasma biomarker evaluations were conducted on the CD4 LQ subgroup and data from the 2.5 and 5.0 g cohorts combined for analysis. Plasma biomarkers included: zonulin, intestinal FABP (I-FABP), sCD14, IL-6, and bacterial flagellin. Pearson correlations were conducted between CD4 cells and plasma biomarkers. Results: Mean plasma IL-6 levels decreased from 2.4 (±3.0) to 0.9 pg/mL (±0.9) (p<0.001) for LQ pts receiving SBI through 24 weeks. Peripheral CD4/CD8 ratio was inversely correlated with plasma IL-6 at week 24 (p=0.02). Change in plasma I-FABP, a marker of enterocyte damage, was correlated to change in plasma flagellin, a marker of microbial translocation, at week 8 (p=0.03) and week 24 (p=0.04). Correlations were also observed with changes in plasma IL-6 and plasma zonulin levels. Mucosal CD4/CD8 levels at week 24 inversely correlated with plasma flagellin (p=0.01). Conclusions: Oral SBI may help decrease translocation of immunogenic substances like flagellin and in turn decrease systemic immune activation and improve CD4/CD8 ratios. SBI may be a novel therapy for reducing immune activation and support mucosal and systemic immune restitution among pts who have not achieved normal CD4 counts despite prolonged suppressive ART. 279 Background: We previously described a novel inflammaging phenotype (IP) in older, HIV-uninfected persons that incorporated plasma biomarkers of intestinal epithelial barrier damage (intestinal fatty acid binding protein), microbial translocation and monocyte activation (soluble (s)CD14), immune activation (sCD27), and inflammation (C-reactive protein). When this classification model was applied to HIV-infected (HIV + ) study participants on anti-retroviral therapy (ART), IP + participants were of a similar age, but had increased levels of plasma IL-6 and LPS and were at higher risk of cardiovascular disease based on Framingham index scores compared to IP - participants. To understand mechanistic pathways involved in inflammaging, we performed a pilot study comparing the plasma proteome in IP + versus IP - ART-treated HIV + persons. Methods: Stored plasma samples were obtained from age (60-67yrs) and sex-matched ART-treated HIV + participants identified in our previous study as IP + (n=6) and IP - (n=6). Participants gave informed consent. SOMAscan proteomics technology was used to identify and quantify plasma proteins. Unpaired t tests were used to compare protein levels between the two groups. Pathway and network analysis was performed using a modified Fisher’s exact test as applied by the Ingenuity Pathway Analysis (IPA) platform. Results: 274 of 1128 proteins measured were significantly different (P<0.05) between IP + and IP - participants with 105 (38%) significantly higher in IP + . Predicted canonical pathways increased in IP + participants were NRF2-mediated Oxidative Stress Responses (p=0.04, activation score=2.3) and Apoptosis Signaling (p=0.07, activation score=1.9). 37 canonical pathways were significantly (p<0.05) decreased. Of the significantly altered proteins, IPA identified 90 with either a direct or indirect biological relationship to IL-6. Of these IL-6-connected proteins, 85 (94%) associated with biological processes of cell proliferation, 79 (88%) with apoptosis and 78 (87%) with necrosis. Proteomic Profiles AssociatedWith an Inflammaging Phenotype During HIV-1 Infection Stephanie M. Dillon 1 ; Eric L. Lee 1 ; BrianVestal 1 ;Tzu L. Phang 1 ; Michael G. Edwards 1 ; CaraWilson 2 1 Univ of Colorado Anschutz Med Campus, Aurora, CO, USA; 2 Univ of Colorado Hosp, Aurora, Aurora, CO, USA

Poster Abstracts

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CROI 2016