CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

243 GLUTAMINOLYSIS AND LIPOPROTEINS KEY FACTORS IN HIV LATE IMMUNE RECOVERY Anna Rull 1 , Isaac Rosado-Sánchez 2 , Esther Rodríguez-Gallego 1 , Joaquim Peraire 1 , Consuelo Viladés 1 , Sergi Veloso 1 , María Peñaranda 3 , Félix Gutiérrez 4 , Jesus Santos 5 , Enrique Bernal 6 , Ricardo Pelazas 7 , Manuel Leal 2 , Francesc Vidal 1 , Yolanda M. Pacheco 2 1 Hospital Universitario de Tarragona Joan XXIII, Tarragona, Spain, 2 Institute of Biomedicine of Seville, Sevilla, Spain, 3 Hospital Universitario de Son Espases, Palma de Mallorca, Spain, 4 Universidad Miguel Hernández de Elche, Elche, Spain, 5 Hospital Virgen de la Victoria, Málaga, Spain, 6 Hospital Universitario Reina Sofia, Murcia, Spain, 7 Hospital Universitario de Canarias, San Cristóbal de La Laguna Background: The immunological, biochemical and molecular mechanisms associated with poor immune recovery are far from known, and metabolomics profiling offers an additional value to traditional soluble markers. Here, we search for predictive markers of late immune response and disease progression in a cohort of HIV-subjects with increased CD4 T-cell turnover and inflammation preceding their poor immune recovery. Methods: We executed a nuclear magnetic resonance (NMR) and mass spectrometry (MS)-based circulating metabolomics approach in 41 cART-naive HIV-infected patients who were initiating cART and subsequently followed up these patients for 96 weeks (n = 17). Random forest (RF) was performed to identify the variables that best partitioned the overall study population according to immune recovery predisposition. Network of metabolite-protein interaction and functional enrichment analyses were generated to identify the metabolomics pathways affected. Results: Plasma L-tyrosine (P = 0.04), L-glutamate (P = 0.05), and phosphatidylcholine (PC) (16:1) (P = 0.01) by univariate model, and hsCRP, IL-6 and palmitoylcarnitine (PalC) by Random Forest, were identified as predictive markers of late immune recovery. After 96 weeks of cART, CD4+ T-cell counts were positively correlated to glycocholic acid (r = 0.51, P = 0.04) and citrulline (r = 0.60, P = 0.03), and inversely correlated to lipopolysaccharide (LPS) (r = -0.61, P = 0.03) and DL-pipecolic acid (r = -0.94, P < 0.01). Compositional and structural changes on HDL and decreased glutamate concentrations were associated to immune recovery during cART. Conclusion: Metabolomics improve the value of soluble parameters and shows novel and relevant data that may contribute to a better understanding of molecular mechanisms preceding discordant response and immunological progression under suppressive stable cART. The metabolomics signature of ART-naïve HIV subjects with late immune recovery is the expression of pro- inflammatory molecules and glutaminolysis, which is probably related to their higher T-cell turnover.

244 EXPANSION OF MYELOID-DERIVED SUPPRESSOR CELLS IN ART- SUPPRESSED HIV-INFECTED PATIENTS Carla Serra Peinado 1 , Laura Luque-Ballesteros 1 , Rein Willekens 2 , Jordi Navarro 2 , Adrià Curran 2 , Joaquin Burgos 2 , Esteban Ribera 2 , Ariadna Torrella 2 , Bibiana Planas 2 , Rosa Badía 2 , Josep Castellví 2 , Vicenç Falcó 2 , María J. Buzón 1 1 Vall d’Hebron Research Institute, Barcelona, Spain, 2 Hospital Universitario de la Vall d’Hebron, Barcelona, Spain Background: The existence of HIV reservoirs represents the main obstacle to cure HIV. The role of the immune system at maintaining and regulating this viral persistence remains largely unknown. Here, we studied the role of the myeloid- derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells with high immunosuppressive effects on the HIV reservoir. Methods: Samples from n=14 ART-suppressed and n=8 heathy controls were included in this study. Frequency of two subpopulation of MDSC (CD3-, CD33+, CD11b+, HLA-DRlow), M-MDSC (CD14+) and G-MDSC (CD14-), was assessed by multiparametric flow cytometry, as well as immune activation in CD4+ and CD8+ T cells (markers CD38 and HLA-DR). The functional status of MDSC was assessed by the expression of Indoleamine 2,3-dioxygenase (IDO) and Arginase-1 (ARG-1). Total HIV-DNA and intracellular HIV-RNA were quantified by qPCR in purified CD4+ T cells. P24 expression and MDSC infiltration in B-cell follicles within lymph nodes of n=2 chronic infected patients was measured by immunohistochemistry. Results: ART-suppressed patients presented significantly higher proportions of M-MDSC compared to healthy controls (0.24% and 0.78 in healthy and ART-suppressed donors, respectively). Importantly, this expanded M-MDSC population showed higher expression of IDO and ARG-1 (MFI of 488 and 628 for IDO, 533 and 685 for ARG-1 in healthy controls and ART-suppressed, respectively), two enzymes highly related with the immunosuppressive capacity of the MDSC. Moreover, the percentage of M-MDSC in ART-suppressed patients positively correlated with the activation of CD4+ and CD8+ T cells (rho=0.830 p=0.0008 for CD4+, and rho=0.741 p=5495 for CD8+), which in turn correlated with intracellular HIV-DNA (rho=0.742 p=0.0140 for CD4+, and rho=0.672 and p=0.0331 for CD8+) and HIV-RNA (rho=0.837 p=0.0095 for CD4+, and rho=0.877 and p=0.0042 for CD8+). Additionally, infiltration of MDSC in B-cell follicles was preferentially observed in association with the expression of p24 (rho=0.372 p=0.039). Conclusion: Overall, in ART-suppressed patients, MDSC might be an important player in the preservation of the HIV-reservoir. Finding new therapeutic strategies to modulate the immunosuppressive actions of the MDSC might significantly impact the HIV reservoir. 245 CIRCULATING Β-D-GLUCAN AND INDUCTION OF IMMUNE ACTIVATION Stéphane Isnard 1 , Rayoun Ramendra 1 , Franck P. Dupuy 1 , VikramMehraj 1 , Rosalie Ponte 1 , Jun Chen 1 , Cecilia Costiniuk 1 , Réjean Thomas 2 , Jean-Guy Baril 3 , Madeleine Durand 4 , Cécile Tremblay 4 , Petronela Ancuta 4 , Nicole Bernard 1 , Don C. Sheppard 1 , Jean-Pierre Routy 1

Poster Abstracts

87

CROI 2019