CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

704 BIOMARKERS AND GENETICS OF CELL CHOLESTEROL DYSREGULATION IN HIV NONPROGRESSORS Giovanna Rappocciolo , Diana Campbell DeLucia, Jeremy J. Martinson, Stacy Wendell, Charles Rinaldo University of Pittsburgh, Pittsburgh, PA, USA Background: Professional antigen-presenting cells (APC) from HIV nonprogressors (NP) are inefficient mediators of HIV-1 trans infection of CD4+ T cells due to altered cell cholesterol metabolism (Rappocciolo, et al., mBio 2014), potentially reducing spread of virus and controlling disease progression. Here, we show the role of host genetic variation and signaling metabolites in control of cell cholesterol homeostasis in NP. Methods: We tested 29 NP (9 elite controllers, 10 long term NP, 10 viremic controllers), 13 HIV progressors (PR) and 10 seronegatives (SN) in the MACS. Plasma-mediated cholesterol efflux (CE) was measured by fluorometry (Biovision). To measure CE from participants APC, B cells and DC were loaded with BODIPY-labelled cholesterol and incubated with apolipoprotein A-1 (APOA1) as a cholesterol acceptor. Levels of apolipoprotein A-II (APOAII) in sera were measured by ELISA. Targeted lipidomics analysis was done by LC-MS on lipid fractions of sera. SNP analysis was performed using TaqMan assays. Results: Plasma from NP and SN showed higher induction of CE than PR (p< 0.008). Similarly, B cells and DC from NP had higher CE to APOA1 than APC from PR (p<0.05). CE from CD4+ T cells was similar among PR, NP and SN. Targeted lipidomic analysis revealed significantly higher levels of 5-oxo-eicosatetraenoic acid (5-oxo-ETE) and PGE2, metabolites of arachidonic acid, in sera from NP compared to PR (p<0.05). Finally, the SNP rs5082 (APOAII c.-265 T>C, located in the APOAII gene) was associated with the NP phenotype (p=0.0003 for a dominant role for the minor allele). Conclusion: NP have a unique combination of metabolic and genetic factors that impact altered cholesterol homeostasis, conferring on their APC the inability to transfer HIV to CD4+ T cells, thus controlling HIV dissemination. In NP we detected higher levels of 5-oxo-ETE, a metabolite produced by B cells and DC. This is a signaling agent that acts in both an autocrine and paracrine fashion and binds PPARγ nuclear receptor, increasing transcription of ABCA1 thus elevating cell CE. We hypothesize that such autocrine signaling could be a mechanism by which APC from NP escape downregulation of CE induced by HIV. The presence of a SNP in the APOAII gene could contribute to higher cholesterol efflux by modifying HDL composition. These data suggest that HIV eradication interventions need to incorporate strategies to shape cell cholesterol content 705 STATIN USE AND CARDIOVASCULAR DISEASE MITIGATION AMONG PERSONS LIVING WITH HIV Derek T. Larson 1 , Seung Hyun Won 2 , Anuradha Ganesan 3 , Ryan Maves 1 , Jason Okulicz 4 , Karl Kronmann 5 , Xiuping Chu 2 , Christina Schofield 6 , Thomas O’Bryan 2 , Brian K. Agan 2 , Robert Deiss 1 1 Naval Medical Center San Diego, San Diego, CA, USA, 2 Uniformed Services University of the Health Sciences, Bethesda, MD, USA, 3 Walter Reed National Military Medical Center, Bethesda, MD, USA, 4 Brooke Army Medical Center, San Antonio, TX, USA, 5 Naval Medical Center Portsmouth, Portsmouth, VA, USA, 6 Madigan Army Medical Center, Takoma, WA, USA

703 THE MEDITERRANEAN PORTFOLIO DIET IN HIV DYSLIPIDAEMIA: A RANDOMIZED CONTROLLED TRIAL Clare Stradling 1 , G N. Thomas 2 , Karla Hemming 2 , Shahrad Taheri 3 , Stephen Taylor 1 , Jonathan Ross 4 , Satyajit Das 5 1 Heart of England NHS Foundation Trust, Birmingham, UK, 2 University of Birmingham, Birmingham, UK, 3 Weill Cornell Medicine College in Qatar, Doha, Qatar, 4 University Hospitals Birmingham, Birmingham, UK, 5 Coventry &Warwickshire Partnership NHS Trust, Coventry, UK Background: The risk of cardiovascular disease is increased in the HIV population, potentially due to the additional burdens of infection, inflammation and antiretroviral treatment (ART). This trial aims to examine the effect of dietary intervention on cardiovascular risk (CVR) in HIV dyslipidaemia. Methods: This pilot, parallel, randomized controlled trial (ISRCTN32090191) recruited adults with stable HIV infection on ART and LDL-cholesterol >3mmol/l from 3 UK centres. Randomization (1:1) compared the effect of dietary advice to reduce saturated fat (Diet1) versus MedDiet with additional cholesterol lowering foods e.g. plant stanols, soya, oats (Diet2). Measurements of CV risk factors, fasting blood lipids, food intake, body composition, and arterial stiffness were conducted at baseline, month 6 and month 12. Between-group changes of CVR factors were assessed using ANCOVA, with adjustments for baseline values of the dependent variables. Analysis was by intention to treat (ITT) and Complier Average Causal Effect. Results: 60 eligible adults were randomized with mean age 42±7years, LDL-cholesterol 3.9±0.6mmol/l, 50% female, 65% non-smokers, 50% black African, 40%white European. Baseline characteristics were comparable between groups. At 6 months, Diet2 participants (n=29) showed a significantly greater reduction in LDL-cholesterol, total to HDL-cholesterol ratio, systolic blood pressure (BP) and increase in Mediterranean Diet Score, than those in Diet1 (n=31), see table. Intake of Mediterranean (olive oil, fish, legumes) and Portfolio foods (nuts, stanols) increased significantly in the Diet2 group (p<0.01). Individual adherence varied from 11 to 100% (mean 59±21%). Body composition, arterial stiffness, gut function, and levels of physical activity were not significantly different between the groups. As expected, the estimated treatment effect among compliers to MedDiet (LDL-cholesterol -0.87mmol/l, 95%CI -1.79 to 0.05) and Portfolio foods (-0.76mmol/l, 95%CI -1.54 to 0.01) appears larger than that for ITT analysis (-0.38mmol/l, 95%CI -0.68 to -0.09). Conclusion: Dietetic advice to follow a Mediterranean diet containing nuts, plant stanols, soya protein, beans and oats produced a greater improvement in diet quality, blood pressure, and a 10% greater reduction in LDL-cholesterol than standard guidelines to reduce saturated fat intake. Analysis assuming full compliance and preserving randomisation suggests a possible doubling of this estimated treatment effect.

Poster Abstracts

CROI 2018 262