CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

679 INFLAMMATION ASSOCIATES WITH IMPAIRED ARTERIAL ELASTICITY IN EARLY HIV DISEASE Tess Peterson 1 , Kathy Huppler Hullsiek 1 , Nicole Wyman Engen 1 , Nagalingeswaran Kumarasamy 2 , Pamela Schreiner 1 , Jason V. Baker 3 1 University of Minnesota, Minneapolis, MN, USA, 2 YR Gaitonde Center for AIDS Research and Education, Chennai, India, 3 Hennepin County Medical Center, Minneapolis, MN, USA Background: HIV-associated inflammation contributes to higher cardiovascular disease (CVD) risk. It is unclear, however, to what degree CVD pathogenesis is influenced very early in HIV infection before significant disease progression. We evaluated dysfunction of the microvasculature as an early measure of CVD pathogenesis via estimates of small arterial elasticity (SAE) and studied associations with inflammatory biomarkers among a subset of participants in the START trial at baseline (i.e., ART-naïve at CD4 counts > 500 cells/µL). Methods: Radial artery waveforms were recorded non-invasively using a tonometer, and SAE was estimated from analysis of the diastolic pulse waveform (CR2000, HDI). Biomarkers (see table) were measured from stored plasma samples using immunoassays and analyzed on a log 2 scale. Linear regression was used to evaluate cross-sectional associations between biomarkers and SAE. In addition to individual assessment, biomarkers were also analyzed simultaneously and in adjusted models that included: sex, age, race/ethnicity, CD4 cell count, HIV viral load, smoking, hypertension, body mass index, high- density lipoprotein cholesterol, and total cholesterol. Results: Among 326 ART-naïve participants, 70%were male, 66%were non-White, 29%were smokers, median (IQR) age was 33 (28, 41), CD4+ cell count was 609 (558, 689) cells/µL, HIV viral load was 4.2 (3.7, 4.7) log 10 RNA copies/mL, and SAE was 8.0 (6.3, 9.8) mL/mmHg x100. In univariable models, higher levels of hsCRP, IL-6, sICAM-1, and D-dimer were associated with lower (more impaired) SAE at baseline (Table). After adjustment for age, sex, and race/ ethnicity, associations with D-dimer and sICAM-1 were no longer statistically significant, and in fully adjusted models including both demographic and clinical characteristics, hsCRP (ß=-0.18, p=0.031) and IL-6 (ß=-0.56, p<0.001) remained associated with SAE. When all biomarkers were evaluated simultaneously, only IL-6 was independently associated with SAE after full adjustment (ß=-0.52, p=0.003). Conclusion: These data suggest that higher levels of systemic inflammation contribute to vascular dysfunction even early in HIV disease when CD4 cell counts are high. Only the association between IL-6 and SAE was independent of other measured biomarkers and traditional CVD risk factors. Extending these cross-sectional data to follow-up data in START is needed to determine if early ART with viral suppression influences the contribution of ongoing HIV- associated inflammation to CVD risk.

signaling dependent on inflammation and reactive oxidative species signaling (ROS). Methods: SMAs were obtained from HIV-infected subjects with virally suppressed on antiretroviral therapy (ART) (n=8) and confounding factors- matched HIV-uninfected individuals (n=6). Both groups had no identified other CVD risk factors. The acetylcholine (ACh)-induced endothelium- derived relaxation (EDR), endothelium derived relaxation factor (EDRF), endothelium derived hyperpolarizing factor (EDHF) were recorded ex vivo in PVAT-intact or denuded SMAs by a wire myograph. Microvascular nitric oxide (NO), generation of cellular and mitochondria ROS were quantitated by Fluorescence RatioMaster system. The malondialdehyde (MDA), NO, cytokines and adipokines were measured in homogenate adipose supernatant. Results: In comparison with the HIV-uninfected, the HIV-infected group had significantly increased (all P<0.05) adipose MDA (15.1 ± 2.5 vs 10.9 ± 2.6 ng/ mg protein), PAI-1 (444 ± 42 vs 291 ± 53 pg/mg protein), INFα2 (423±49 vs 286±33 pg/ml/mg protein), IL-1α ( 5.5±3.8 vs 1.3± 0.7 pg/ml/mg protein) and IL-9 (8.8±1.4 vs 5.1± 0.8 pg/ml/mg protein) and reduced adiponectin (2.1 ± 0.3 vs 3.1 ± 0.4 ng/mg protein).Their PVAT-denuded vessels from HIV group had an impaired responses to ACh-induced EDR (53±2% vs 75±2%), EDRF (26±3% vs 39±2%), NO generation (0.21±0.03 vs 0.58± 0.1 fluoresce unit) and increased cellular ROS (Δ0.32 ± 0.05 vs 0.10 ± 0.02 fluoresce unit) and mitochondria ROS (Δ0.10 ± 0.04 vs 0.18 ± 0.04 fluoresce unit). Whereas, the vessels with PVAT has enhanced EDR, EDRF and NO only in controls. These beneficial effects of PVAT were lost in vessels from HIV-infected group. Conclusion: HIV-infected individuals have increased intrinsic vascular defects from ROS. They also have adipose inflammation leading to reduction of beneficial microvascular PVAT signaling.To prevent the cardiovascular morbidity of HIV infection, therapeutic targets should include elimination of ROS and inflammation and its extravascular actions on PVAT. 681 PCSK9 LEVELS IN RELATION TO IMMUNE ACTIVATION AND SUBCLINICAL CORONARY PLAQUE IN HIV Markella V. Zanni 1 , Lauren Stone 2 , Mabel Toribio 2 , Dodie Rimmelin 2 , Jake A. Robinson 3 , Tricia H. Burdo 3 , Kenneth C. Williams 4 , Kathleen V. Fitch 2 , Janet Lo 2 , Steven K. Grinspoon 2 1 Massachusetts Department of Public Health, Boston, MA, USA, 2 Massachusetts General Hospital, Boston, MA, USA, 3 Temple University, Philadelphia, PA, USA, 4 Boston College, Chestnut Hill, MA, USA Background: Proprotein convertase subtilisin /kexin 9 (PCSK9) is known to mediate homeostasis of low density lipoprotein cholesterol (LDL-c), but may also participate in immune reactivity and atherogenesis. A pro-inflammatory milieu stimulates diverse cell types to release PCSK9 into the circulation. Conversely, PCSK9 may elicit pro-inflammatory responses in monocytes/ macrophages, with relevance to immune-mediated atherogenesis. In the general population, PCSK9 levels relate to major adverse cardiovascular events, even after controlling for LDL-c levels. We endeavored to assess whether PCSK9 levels would be elevated among asymptomatic individuals with HIV (vs. without HIV) in relation to levels of systemic monocyte activation markers and/or subclinical coronary atherosclerotic plaque parameters. Methods: We compared PCSK9 levels among asymptomatic individuals with and without HIV. As individuals with HIV are known to have high-level systemic immune activation and an increased subclinical coronary atherosclerotic plaque burden, we therefore assessed whether PCSK9 levels related to levels of systemic monocyte activation markers and/or to subclinical coronary atherosclerotic plaque parameters within each group. Levels of systemic monocyte markers were measured using ELISA and plaque was assessed using coronary computed tomography angiography. Results: PCSK9 levels were higher among HIV-infected (n=149) vs. matched non-HIV-infected subjects (n=69) [332 (272, 412) ng/mL vs. 304 (257,375) ng/mL; P = 0.047]. Among non-HIV-infected subjects, PCSK9 levels related significantly to age (rho = 0.35; P = 0.003) and to Framingham Point Score (rho = 0.51; P<0.0001). Among HIV-infected subjects, PCSK9 levels related to Framingham Point Score (rho = 0.33; P<0.0001) and LDL-c (rho = 0.16; P = 0.05). Further, among the HIV-infected group, significant positive associations were noted between PCSK9 levels and levels of systemic monocyte activation markers including sCD14 (rho = 0.22; P = 0.009) and sCD163 (rho = 0.23; P = 0.006). PCSK9 levels did not relate to subclinical coronary atherosclerotic plaque parameters either in the group with or without HIV.

Poster Abstracts

680 PERIVASCULAR ADIPOSE INFLAMMATION AND MICROVASCULAR ENDOTHELIAL DYSFUNCTION IN HIV Cheng Wang , Tian Li, Philena Sun, Cuiwei Wang, Seble Kassaye, Princy Kumar, Jennifer Verbesey, Mary Young, Christopher Wilcox, Dan Wang Georgetown University, Washington, DC, USA Background: Perivascular adipose tissue (PVAT) surrounds most vessels in the human body and is a major player in regulating vascular reactivity. We reported previously an enhanced vascular contraction and endothelial dysfunction in subcutaneous microvascular arterioles (SMAs) dissected from a gluteal skin biopsy in HIV infected individuals. This study aims to further examine whether this HIV- associated microvascular dysfunction is caused by impaired PVAT

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