CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: The data suggest previously unnoticed synergistic interactions between intracellular DNA and RNA sensing pathways in cDC in some EC, probably affected by genetic polymorphisms in molecules involved in nucleic acid sensing in these individuals. 261 PROTEOMIC PROFILE ASSOCIATED WITH LOSS OF SPONTANEOUS HIV-1 ELITE CONTROL Laura Tarancon-Diez 1 , Esther Rodríguez-Gallego 2 , Felipe Garcia 3 , Verónica Alba 2 , Jorge Romero 4 , José Miguel Benito 5 , Pol Herrero 2 , Anna Rull 2 , Beatriz Dominguez-Molina 1 , Joaquim Peraire 2 , Consuelo Viladés 2 , Manuel Leal 1 , Francesc Vidal 2 , Ezequiel Ruiz-Mateos 1 , for the ECRIS integrated in the Spanish AIDS Research Network 1 Institute of Biomedicine of Seville, Sevilla, Spain, 2 Hospital Universitario de Tarragona Joan XXIII, Tarragona, Spain, 3 Hospital Clinic of Barcelona, Barcelona, Spain, 4 Centro Sandoval, Madrid, Spain, 5 Fundacion Jimenez Diaz, Madrid, Spain Background: Elite Controllers (EC) spontaneously control plasma HIV-1- RNA without antiretroviral therapy (cART). However, 25% lose virological control over time. Recent findings have identified Transient Controllers (TC) as subjects with low Gag-specific T-cell polyfunctionality, high viral diversity and high proinflammatory cytokine levels. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers. Methods: Plasma samples from TC (EC who spontaneously lost virological control, n=8) at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n=8). Comparative plasma shotgun proteomics was performed with TMT isobaric tag labeling and nanoflow liquid chromatography coupled to Orbitrap mass spectrometry. Results: Eighteen proteins exhibited differences comparing PC and pre-loss TC time points (Figure A). These proteins were involved in proinflammatory mechanisms and some of them play a role in HIV-1 replication and pathogenesis and interact with structural viral proteins. A good differentiation between groups was observed with the proteins Coagulation factor XI (FA11), Alpha-1- antichymotrypsin (AACT), Ficolin-2 (FCN2), 14-3-3 zeta/delta protein (1433Z) and Galectin-3-binding protein (LG3BP) (Figure B), considered potential biomarkers. We compared the levels of those five proteins by western blot in non-infected healthy donors, viremic HIV-infected patients with progressive disease and HIV-1-infected patients on supresive cART (n=8 of each group). TC and viremic HIV-infected patients showed a similar trend in most of the protein levels, while protein profile in PC were comparable to uninfected patients and somehow to patients on supresive cART (Figure C). Conclusion: The proteomic profile associated with the loss of virological control was characterized by higher levels of inflammation, transendothelial migration and coagulation. These proteins, especially Galectin-3-binding protein, could be considered as potential biomarker for the prediction of virological progression as well as members of this mechanistic pathways can be considered good candidates for potential drug targets for achieving persistent control. This finding enhances the recent idea that suggests that HIV controllers is a heterogeneous group of subjects being persistent controllers a good model of functional cure.

262 ANTI-GP120 ANTIBODY TITRES CORRELATE WITH AB-DEPENDENT FUNCTIONS IN HIV CONTROLLERS Sanket Kant 1 , Franck P. Dupuy 1 , Chris Leeks 1 , Alexandre Barbe 2 , Ningyu Zhang 1 , Cindy X. Zhang 1 , Jean-Pierre Routy 1 , Petronela Ancuta 3 , Cécile L. Tremblay 3 , Nicole Bernard 1 1 McGill University Health Centre Research Institute, Montreal, QC, Canada, 2 Paris Descartes University, Paris, France, 3 Centre de Recherche du CHUM, Montreal, QC, Canada Background: Post-antigen (Ag) recognition, the Fc portion of antibodies (Abs) activates the complement cascade and also binds to Fc receptors (FcRs) on innate immune cells such as monocytes, triggering phagocytosis and natural killer (NK) cells inducing target cell lysis. Elite controllers (EC) and viremic controllers (VC) are treatment-naïve HIV+ individuals who maintain viral loads (VL) <50 copies/ml plasma (c/mlp) and <3000 c/mlp, respectively. Ab- dependent (AD) functions have been implicated in playing a role in HIV control. Thus, EC & VC would differ from HIV+ untreated progressors (UTP, VL>2000c/ mlp), antiretroviral therapy (ART) treated individuals (TP, VL<50c/mlp) in terms of anti-HIV envelope (gp120)-specific IgG functionality. Here, we compared Abs in plasma from these groups that mediate AD complement deposition (ADCD), AD cellular phagocytosis (ADCP) and AD cellular cytotoxicity (ADCC). Methods: Total IgG and anti-gp120 IgG concentrations in plasma from 18 UTP, 24 TP, 36 EC and 16 VC were quantified by ELISA. ADCD and ADCC assays assessed the frequency of HIV-infected CEM.NKr.CCR5 (iCEM) target cells (T) positive for the cell surface C3b complement component and annexin V (AnV), respectively. The ADCP assay measured the phagocytosis of gp120-coated fluorescent beads by THP-1 (E) monocyte-like cells. Activity was expressed as the area under the curve (AUC) of the ADCD and ADCP score (% fluorescent T/E x mean fluorescence intensity (MFI) of T/E), respectively for 2 plasma IgG concentrations. The ADCC readout was expressed as the AUC of the frequency AnV+ T for 2 plasma IgG concentrations. Pooled plasma from HIV+ and HIV- individuals were used as positive and negative controls, respectively. Results: UTP, EC and VC had significantly higher concentrations of anti-gp120 specific Abs than TP (p<0.0001, Kruskal-Wallis tests with Dunn’s post tests). No statistically significant differences were found between UTP, EC and VC groups for the 3 AD assays, but each was significantly higher than results for plasma from TP (p<0.001 for all, Dunn’s). When ADCD, ADCC and ADCP results were normalized to the concentration of each sample’s anti-gp120 Ab, between group differences disappeared. Conclusion: High concentrations of anti-gp120 Abs resulted in higher AD functions in UTP, EC and VC compared to TP. Therefore, between group differences in these AD functions are attributed to the between-group differences anti-gp120 Ab concentrations rather that AD function potency. Background: The benefits of antiretroviral therapy (ART) for HIV controllers (HCs) remain unclear, but studies have shown that HCs with low CD4+ T cell counts have very high levels of immune activation. Immune activation is classically measured by the dual expression of HLA-DR and CD38 on T cells, but a subset of activated cells, HLA-DR+CD38- CD8+ T cells, are thought to play a role in elite control. Here, we measured HLA-DR and CD38 expression pre and post ART initiation in 3 HCs with low CD4 cell counts to assess the contribution of low level viremia to immune activation. Methods: HLA-DR and CD38 expression on CD4+ and CD8+ T cells and NK cells was determined by flow cytometry in 2 VCs (VC19 and VC20) and a post treatment controller (PTC2) with low CD4+ T cell counts. Results at baseline and after 2 weeks of ART were compared to historical controls: elite controllers (EC) n=8, chronic progressors (CP) n=11 and HIV negative subjects (HN) n=16. Pre and post therapy viral loads (VL) were measured and compared to changes in immune activation. Results: All data is presented in the order of VC19, VC20 and PTC2, respectively. Despite low baseline VL (509, 395 and 1073 copies/ml), CD4+ T cell counts in all 3 HCs were low (254, 154, and 77 cells/ul). Two weeks of ART dropped VL in all 3 HCs to < 50 copies/ml. The median percentage of HLA-DR/CD38 co-expression on CD4+ T cells, CD8+ T cells and NK cells was < 5 in ES, CP and HN controls. It was however elevated in all 3 HCs (5, 37 and 12% of CD4+ T cells, 26, 47 and 11% of CD8+ T cells, and 17, 31 and 7% of NK cells). There was a marked decline (> 263 RAPID DECLINE OF IMMUNE ACTIVATION WITH ART IN HIV CONTROLLERS WITH LOW CD4 COUNTS Abena Kwaa , Eileen P. Scully, Joel Blankson Johns Hopkins Hospital, Baltimore, MD, USA

Poster Abstracts

94

CROI 2019