CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: Among asymptomatic individuals with HIV, PCSK9 levels are elevated and related to systemic markers of monocyte activation but not to coronary plaque. Additional studies are needed to determine effects of PCSK9 on immune activation and atherogenesis in HIV and to assess whether PCSK9 inhibition reduces immune activation and coronary plaque burden. 682 AN IMMUNOLOGICAL SIGNATURE FOR SUBCLINICAL ATHEROSCLEROSIS IN HIV-1 INFECTION Tomas Raul Wiche Salinas , Yuwei Zhang, Annie Gosselin, Mohamed El-Far, Inna Bacearnicova, Carl Chartrand-Lefebvre, Madeleine Durand, Cécile Tremblay, Petronela Ancuta Centre de Research du Centre Hospitalier de l’Université de Montreal, Montreal, QC, Canada Background: Immunological alterations causing gut microbial translocation and chronic immune activation may contribute to accelerated cardiovascular disease (CVD) occurrence in HIV-infected individuals on antiretroviral therapy (ART). Here, we sought to identify an immunological signature associated with subclinical atherosclerosis using samples from the Canadian Cohort of HIV and Aging. Methods: Blood was available from HIV-infected on ART (HIV+) and uninfected (HIV-) participants, without CVD diagnosis/symptoms at inclusion. Coronary Artery Calcium Score (CACS), total plaque volume (TPV), and low attenuated plaque volume (LAPV, high-risk atherosclerotic lesions) were determined by CT angiography. Markers of microbial translocation (LBP), mucosal damage (I-FABP), immune activation (sCD14), chemokines (CCL20, CX3CL1, CCL25, MIF) were quantified in plasma by ELISA. Flow cytometry identified subsets of CD4+ T-cells (Th1, Th17, Tregs), monocytes (classical, intermediate, non-classical), and plasmacytoid dendritic cells (pDC) and measured expression of chemokine receptors involved in atherosclerotic plaque formation (CCR2, CCR6, CCR9, CX3CR1). Results: HIV+ (n=71; infection time: 16±8 years; ART duration: 13±8 years; CD4 counts: 551±251 cells/µl; plasma viral load <50 HIV-RNA copies/ml) vs. HIV- (n=26) were similar in age (55±7 vs. 58±8 yrs), Framingham scores (11.1±6.1 vs. 9.9±3.6), and coronary plaque prevalence (42/71 vs. 16/26). However, HIV+ vs. HIV- had higher TPV (369±519 vs. 271±568), LAPV (114±172 vs. 85±171), and CACS (215±385 vs. 174±456; mean±SD). This coincided with increased plasma levels of I-FABP, sCD14, CCL20, and CX3CL1; predominant Th1 and Tregs vs. Th17; reduced frequency of intermediate monocytes with low CCR2 expression; and reduced frequency of CCR9+ pDC. Among HIV+, Th17 frequency negatively correlated with CACS (p=0.011, r=-0.348,), TPV (p=0.005, r=-0.378), and LAPV (p=0.003, r=-0.402); Th17/Th1 ratios negatively correlated with CACS (p=0.03, r=-0.29), TPV (p=0.04, r=-0.27), and LAPV (p=0.05, r=-0.26); and Th7/Tregs ratios negatively correlated with CACS (p=0.034, r=-0.292), TPV (p=0.01, r=-0.346) and LAPV (p=0.006, r=-0.372). Finally, Th17 frequency was negatively correlated with D-dimer levels (p=0.03, r=-0.252). Conclusion: The paucity of blood Th17 cells correlated with subclinical coronary atherosclerosis in HIV+ individuals on ART. This suggests a link between the “leaky gut” caused by Th17 depletion and the development of HIV-associated CVD. 683 CARDIAC MORBIDITY IN HIV IS ASSOCIATED WITH CHECKPOINT INHIBITOR LAG3 Suresh Pallikkuth 1 , Bagavathi Kausalya 2 , Rajendra Pahwa 1 , Shanmugam Saravanan 2 , Li Pan 1 , R Vignesh 2 , Syed Iqbal 2 , Sunil S. Solomon 3 , Kailapuri G. Murugavel 2 , Selvamuthu Poongulali 2 , Nagalingeswaran Kumarasamy 2 , Savita Pahwa 2 1 University of Miami, Miami, FL, USA, 2 YR Gaitonde Center for AIDS Research and Education, Chennai, India, 3 Johns Hopkins Hospital, Baltimore, MD, USA Background: Cardiovascular disease (CVD) is a major contributor to mortality and morbidity in HIV infection. Elevated expression of certain checkpoint inhibitor (CPI) molecules (e.g. PD-1, TIGIT, LAG3, TIM3) on T cells is associated with dampened immunity. Recent evidence for expression of receptors for CPI at the tissue level with selective enrichment of LAG3 receptors in the heart point to a control mechanism for organ immune homeostasis, (Rev Immunity 44, 2016). This study was aimed at defining relationship of CPI and CVD in HIV infection. Methods: Study participants were recruited in YRG CARE, Chennai, India. ART naive viremic, (Gp1, n=102) and ART experienced aviremic (Gp2, n=172) were compared to healthy volunteers (Gp3, n=64) in a cross-sectional analysis

of cardiac function (radial pulse wave and c-IMT)and immunologic markers including CPI on CD4 and CD8 T cells (flow cytometry). Results: In Gp1 findings of CVD were significant (Mann-Whitney’ U test) for lower cardiac ejection time, stroke volume, stroke volume index, cardiac output and small arterial elasticity with higher systemic vascular resistance compared to Gp2 and Gp3. Large arterial elasticity was lower in Gp1 comparison to Gp2. Gp1 had significantly (p<0.0001) higher frequencies than Gps 2 and 3 respectively of CD4 T cells expressing LAG3 (Gps 1, 2, 3: 4.9±3.4, 2.5±1.5, 2.4±1.3) and PD1 (Gps 1, 2, 3: 6.2±7.3,1.5±2.5, 0.9±1.6) while those of TIGIT and Tim 3 were equivalent among groups. Shown in table 1 is Pearson Correlation analysis on log 10 transformed data. Frequencies of CD4+ T cells positive for LAG3, PD1, and for dual expression of LAG3 plus PD1 were inversely correlated in Gp1 with cardiac ejection time, cardiac output, cardiac index, stroke volume, stroke volume index and systemic vascular resistance and in Gp 2 with large artery elasticity, and except for PD1, also with small artery elasticity. Conclusion: In ART naive HIV subjects continuous antigenic stimulation of the immune system results in upregulation of multiple CPI molecules. Our finding of the association of LAG3 and PD1 expressing CD4 cells in cardiac morbidity points to a dominant role of these pathways in regulating cardiac health, given that LAG3 receptors are enriched at the tissue level in the heart. Investigations to understand the immune mechanisms involved could provide insight into potential role of LAG3 immunotherapy (which is in early clinical trials in cancer) in prevention or treatment of cardiac dysfunction in HIV.

Poster Abstracts

684LB IMPACT OF METHOTREXATE ON ARTERIAL INFLAMMATION IN PERSONS WITH TREATED HIV Ahmed Tawakol 1 , Heather Ribaudo 2 , Amorina E. Ishai 1 , Ashley McKhann 2 , Daniel H. Solomon 3 , Zahi A. Fayad 4 , Steven G. Deeks 5 , Michael M. Lederman 6 , Steven K. Grinspoon 1 , James H. Stein 7 , Paul M. Ridker 3 , Judith S. Currier 8 , Priscilla Hsue 5 1 Massachusetts General Hospital, Boston, MA, USA, 2 Harvard University, Boston, MA, USA, 3 Brigham and Women’s Hospital, Boston, MA, USA, 4 Mt Sinai School of Medicine, New York, NY, USA, 5 University of California San Francisco, San Francisco, CA, USA, 6 Case Western Reserve University, Cleveland, OH, USA, 7 University of Wisconsin–Madison, Madison, WI, USA, 8 University of California Los Angeles, Los Angeles, CA, USA Background: Arterial inflammation, a key driver of atherosclerotic cardiovascular disease (ASCVD), is elevated in individuals living with HIV and is hypothesized to underpin the increased incidence of ASCVD in this population. Low-dose methotrexate (LDMTX) is an anti-inflammatory drug that is associated with lower risk of ASCVD in individuals with rheumatoid arthritis. We evaluated the impact of LDMTX on arterial inflammation in treated HIV infection. Methods: We conducted a randomized placebo-controlled trial in ART-treated HIV-infected individuals age ≥40 years with or at increased risk for ASCVD and with CD4+ T-cells >400 cells/mm 3 . Participants received weekly LDMTX or placebo for 24 weeks; both groups received 1 mg folate daily. Arterial inflammation was assessed using FDG PET/CT imaging at 0 and 24 weeks, and measured as standardized uptake values (SUV). SUV was additionally corrected for background activity, producing target-to-background-ratios (TBR). The primary endpoint was ΔTBR. Additionally, a pre-specified secondary endpoint was ΔSUV (which is less susceptible to variation and may associate better with histological evidence of inflammation). Intent to treat group comparisons used stratified Wilcoxon tests. Results: A total of 28 individuals, from 8 sites, provided evaluable image sets. Participants had a median [IQR] age of 55 [51, 62] years, 25 were male, and entry CD4+ T cells of 681 [581, 871] /mm 3 . For the primary endpoint,

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