CROI 2016 Abstract eBook

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Poster Abstracts

Results: 117 participants were enrolled (mean age 60.3 years; 70%male, 59% black, 38%white, non-Hispanic; mean BMI 28.6 kg/m 2 ; mean length of time since diagnosis 15.3 years, mean current CD4 count 691 cells/mm 3 ). Results from all 4 physical performance tests showed significantly impaired performance when compared to normal reference ranges for HIV-uninfected adults matched by age and gender. Short-chain acylcarnitines, including odd chain length dicarboxyls representing incomplete oxidation products of amino acid metabolism, were negatively associated with 8-foot walk speed and positively associated with the co-morbidity index. C18 acylcarnitines were positively associated with several functional measures, including the 30-second chair stand, 6-minute walk and 8-foot walk speed. Long-chain dicarboxyl acylcarnitines were positively associated with the co-morbidity index. The amino acids serine and methionine were negatively associated with the co-morbidity index. Conclusions: Older HIV-infected persons have diminished physical performance compared to HIV-uninfected controls. Individual metabolites appear to be associated with impaired physical performance and a higher comorbidity index, including the dicarboxyl short and long chain acylcarnitines which have been associated with excess mortality in other populations. Further study will be required to assess the significance of these associations. 706 Superior Glucose Tolerance and Metabolite Profiles inWomen vs Men on Long-term ART John R. Koethe 1 ; Cathy Jenkins 2 ; Chris Petucci 3 ; Jeffrey Culver 3 ; Bryan E. Shepherd 4 ; Spyros A. Kalams 1 ;Timothy R. Sterling 1 1 Vanderbilt Univ Sch of Med, Nashville, TN, USA; 2 Vanderbilt Univ, Nashville, TN, USA; 3 Sanford Burnham Prebys Metabolomics Core at the Southeast Cntr for Integrated Metabolomics, Gainesville, FL, USA; 4 Vanderbilt Inst for Global Hlth, Nashville, TN, USA Background: HIV-infected men on antiretroviral therapy (ART) are at higher risk of incident diabetes mellitus compared to women in some epidemiologic studies. We used a metabolomics approach to determine whether a sex difference in plasma amino acids, acylcarnitines, and organic acids predictive of diabetes and impaired energy metabolism is present in healthy, HIV-infected males versus females on the same ART regimen with long-term virologic suppression. Methods: We enrolled 70 HIV patients (43% female) on efavirenz, tenofovir, and emtricitabine (Atripla) with HIV-1 RNA <50 copies/mL for over 2 years, a CD4+ count >350 cells/ µL, and no history of diabetes, cardiovascular disease, statin use, or heavy alcohol use. Hemoglobin A1c (HbA1c) and homeostatic model assessment 2 (HOMA2) fasting insulin sensitivity were measured. Liquid chromatography/mass spectrometry was used to quantitate fasting plasma branched chain and aromatic amino acids (isoleucine, leucine, valine, phenylalanine, and tyrosine) predictive of incident diabetes in the Framingham cohort, and C3 and C5 acylcarnitinines and organic acids indicative of impaired energy metabolism. We assessed the relationship of sex and metabolic parameters using regression models adjusted for age, race, CD4+ count, smoking, duration of ART, and fat mass index (FMI; defined as DEXA total fat [kg] / height [m] 2 ). Results: The median age was 45 years (IQR 39, 50) and median CD4+ count 701 cells/µL (IQR 540, 954). Males and females did not differ by race distribution, smoking prevalence, or median age, body mass index (BMI), CD4+ count, or duration of ART. HbA1c was <6.5% for all participants, indicating adequate insulin release, and did not differ by sex. However, females had higher HOMA2 insulin sensitivity compared to males (p<0.01), and lower plasma levels of isoleucine, leucine, valine, and phenylalanine (p<0.01 for all), and tyrosine (p=0.06). Females also had lower C3 and C5 acylcarnitines (p<0.01 for all), but no difference in alpha-hydroxybutyrate, compared to men. Results were similar when FMI was replaced with BMI in the model. Conclusions: Women on Atripla with long-term virologic suppression had superior glucose tolerance and lower plasma metabolomic biomarkers associated with diabetes risk compared to men. Further studies are needed to determine how these findings compare to HIV-infected individuals on other ART regimens and HIV-uninfected persons, and whether they could reflect sex-differences in regional, hepatic or myocellular adiposity. 707 Reduced Dicer and Brown Adipose Tissue (BAT) Gene Expression in HIV Lipodystrophy MartinTorriani 1 ; Suman Srinivasa 1 ; Kathleen Fitch 1 ;ThomasThomou 2 ; KimberlyWong 1 ; Eva Petrow 1 ; Aaron M. Cypess 3 ; Steven K. Grinspoon 1 1 Massachusetts General Hosp, Boston, MA, USA; 2 Joslin Diabetes Cntr, Boston, MA, USA; 3 NIDDK, NIH, Bethesda, MD, USA Background: HIV patients are at increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood. BAT plays a key role to enhance energy expenditure (EE). The endoribonuclease Dicer has been linked recently to modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicer knockout mice develop lipodystrophy and transformation of BAT to white adipose tissue (WAT). Thus, we hypothesized that reduced Dicer and BAT gene expression from abdominal subcutaneous (SC) WAT would relate to severity of the HIV lipodystrophic phenotype. Methods: 18 HIV (9 with and without clinically apparent lipodystrophy, marked by excess dorsocervical adipose tissue [DCAT]) and 9 non-HIV subjects underwent punch biopsy of the abdominal SC adipose tissue in a cross-sectional study. We assessed abdominal SC WAT specific expression of Dicer and other adipose related genes. The Wilcoxon test was used to compare HIV and non-HIV groups and HIV with and wtihtout excess DCAT as confirmed by MR imaging. Correlations were assessed by Spearman’s. Results: HIV subjects with long duration of HIV and ART use demonstrated excess DCAT vs. non-HIV subjects (9.8±1.0 vs. 6.6±0.8 cm 2 , P=0.02) with similar BMI. Dicer expression was decreased in HIV vs. non-HIV (median[IQR] 4.9 [1.9,11.9] vs. 17.7 [10.7,47.9], P=0.01), as were PGC1a, ZIC1, PRDM16, DIO2, and HSP60 (all P<0.03). Dicer expression was decreased in HIV with vs. without excess DCAT (2.5 [0.0,4.9] vs. 11.2 [4.8,21.5], P=0.006) in addition to brown [PGC1a (P=0.002), ZIC1(P=0.004), LHX6 (P=0.03), PRDM16 (P=0.001), PAT2 (P=0.008), P2RX5 (P=0.02)], beige [TMEM26 (P=0.004), CD137 (P=0.008)] and other genes [DIO2 (P=0.002), leptin (P=0.003), HSP60(P=0.0004)]. Among all subjects, downregulation of Dicer correlated with downregulation of UCP1, PGC1a, ZIC1, LHX8, PRDM16, PAT2, P2RX5, TMEM26, CD137, DIO2, leptin, and HSP60 (all P<0.01). Excess DCAT negatively correlated with PGC1a, ZIC1, LHX8, PRDM16, PAT2, P2RX5, TMEM26, DIO2, leptin and HSP60 (all P<0.04). Resting EE normalized to fat free mass correlated with UCP1, LXH8, PAT2, TMEM26, and HSP60 (all P<0.04). Conclusions: Our results demonstrate reduced Dicer in relationship to downregulation of multiple BAT related genes in SC WAT in HIV lipodystrophic patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase “browning” of WAT may yield a novel target to improve cardiometabolic health in HIV.

Poster Abstracts

293

CROI 2016