CROI 2016 Abstract eBook
Atorvastatin (ATV) response signature among ATV-responders (R) and ATV non- responders (NR). A- shows ISG filter; to 50 genes baseline, B- network inference C – shows pink for- ATV non responders and blue for ATV responders
298 ACE-Inhibitors to Decrease Lymphoid Fibrosis and the Size of the Latent Reservoir
Leslie R. Cockerham 1 ; Ma Somsouk 2 ; Sunil K. Joshi 3 ; Sharon R. Lewin 4 ; Steven A.Yukl 3 ; Ajantha Rhodes 5 ; Elizabeth Sinclair 2 ; Marc Hellerstein 6 ; Steven G. Deeks 2 ; Hiroyu Hatano 2 1 Med Coll of Wisconsin, Milwaukee, WI, USA; 2 Univ of California San Francisco, San Francisco, CA, USA; 3 San Francisco VA Med Cntr, San Francisco, CA, USA; 4 Doherty Inst for Infection and Immunity, Univ of Melbourne, Melbourne, Australia; 5 Univ of Melbourne, Melbourne, Australia; 6 Univ of California Berkeley, Berkeley, CA, USA Background: In HIV infection, lymphoid architecture is disrupted by fibrosis and this persists during antiretroviral therapy (ART). The role of anti-fibrotic agents in HIV-infection is therefore an area of active investigation. Studies have shown that ACE inhibitors have anti-fibrotic properties through inhibition of transforming growth factor-β1. We completed a randomized, placebo-controlled, pilot study to assess whether the addition of lisinopril to ART reverses fibrosis in gut-associated lymphoid tissue (GALT), and whether this leads to more effective host immune responses and reduction of the latent reservoir. Methods: Thirty HIV-infected individuals on ART (<75 copies/mL) for ≥1 year were randomized to lisinopril 20mg daily or matching placebo for 24 weeks. All subjects were male. Enrollment was stratified by CD4 + T cell counts of <350 cells/mm 3 (non-responders, NRs) and ≥ 350 cells/mm 3 (immunologic responders, IRs). The primary end point was the change in collagen turnover in rectal biopsies from baseline. Heavy water labeling was used to quantify a fractional synthesis rate of collagen in GALT using liquid- chromatography-mass spectrometry. Secondary outcomes included the change in: 1) CD4 + and CD8 + total Gag-specific responses (IFN-γ, IL-2, TNF- α, or CD107a) in GALT and peripheral blood mononuclear cells (PBMCs); 2) the percentage of CD38 + HLA-DR + CD4 + and CD8 + T cells in GALT and PBMCs; and 3) HIV RNA and DNA levels in GALT and PBMCs. Levels were compared using the Wilcoxon rank sum test. Results: Collagen turnover rates did not differ significantly between the two treatment arms. The addition of lisinopril did not have a significant effect on the change in CD4 + and CD8 + Gag-specific responses, T cell activation, or in the levels of HIV RNA or DNA in either GALT or PBMCs. Likewise, no difference was obsrved between IRs and NRs in the response to lisinopril. NRs did have increased levels of CD38 + HLA-DR + CD4 + and CD8 + T cells in GALT at baseline compared to IRs (CD4: 14.8% vs 8.2%, p=0.008; CD8: 28.6% vs 19.7%, p=0.09). CD4 + T cell activation in GALT correlated negatively with peripheral CD4 + T cell count (rho= -0.47, p=0.009). Conclusions: Treatment with lisinopril for 24 weeks in HIV-infected adults did not result in a significant change in collagen turnover, HIV-specific responses, T cell activation or HIV RNA or DNA in either GALT or PBMCs. Further study is needed to see if anti-fibrotic agents may be useful in reversing lymphoid fibrosis and reducing the size of the HIV reservoir. 299 Distinctive Dynamics of Phenotypic Cellular Restoration in IRIS Pablo F. Belaunzarán-Zamudio 1 ; Livio Azzoni 2 ; David H. Canaday 3 ;Yanink Caro-Vega 4 ; Brian Clagget 5 ; Benigno Rodriguez 6 ; Juan Sierra-Madero 7 ; Ian M. Sanne 8 ; Irini Sereti 9 ; Michael M. Lederman 5 1 Inst Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico; 2 The Wistar Inst, Philadelphia, PA, USA; 3 Cleveland VA Med Cntr, Cleveland, OH, USA; 4 Inst Nacional de Ciencias Médicas y Nutrición, Salvador Subirán, Mexico, Mexico; 5 Case Western Reserve Univ, Cleveland, OH, USA; 6 Case Western Reserve Univ Sch of Med, Cleveland, OH, USA; 7 Natl Inst of Med Scis and Nutrition Salvador Zubirán, Mexico City, Mexico; 8 Univ of the Witwatersrand, Wits Hlth Consortium, Johannesburg, South Africa; 9 NIH, Bethesda, MD, USA Background: IRIS is a common and potentially fatal complication of ART initiation in advanced AIDS; its immunopathogenesis remains poorly understood. While the clinical manifestations and underlying pathogenic mechanisms might vary for each IRIS-associated-pathogen, some studies suggest common inflammatory mechanisms. Here, we characterize the dynamics of lymphocyte maturation phenotypes, CCR5 expression and activation status of circulating T cells in patients who did and didn’t develop IRIS. Methods: Lymphocyte phenotypes were monitored at baseline and weeks 4,12, 24 and 48 by flow cytometry on cryopreserved PBMC obtained from 40 patients initiating ART plus maraviroc or placebo in a substudy of the CADIRIS trial. Results: Randomization to maraviroc had no effect on occurrence of IRIS. Twelve (30%) subjects developed IRIS. Patients with IRIS had a significantly greater CD4 cell increase at Weeks 4, 12 and 24 that were mostly effector memory (EM) cells. EM numbers were greater in IRIS patients than those without IRIS at weeks 4 (13168/mL vs 6308, p = 0.01), 12 (13,274 vs. 8415, p = 0.027) and 24 (15281.4 vs . 6960.8, p < 0.001). Thereafter EM numbers fell and were comparable in the groups at week 48. No differences were observed in naïve (N), Central Memory (CM) and Terminally Differentiated (TD) CD4 cells. The proportion of activated (CD38+DR+) CD4+cells also increased more during the first 4 weeks in patients with IRIS than in patients without (+12.6% vs . 3.2%, p = 0.04), and were significantly different at week 4 (45.9% vs. 37.2%, p =0.05). Also, a higher proportion of the CD4+ EM cells in patients with IRIS expressed activation markers (CD38+DR+) than was seen in patients without IRIS (+12.9 vs. +3.03%, p =0.08), but no differences were observed for other CD4 maturation subtypes. There were no differences in the proportion of CD4+ and CD8+ T cells expressing CCR5 by group at any time point perhaps reflecting the failure of maraviroc to affect IRIS occurrence. Absolute CD8 cells, CD8 maturation subtypes and activated maturation subtypes declined throughout the study in both groups similarly. Conclusions: These results suggest that that activated CD4 effector memory cells might participate in the immunopathogenesis of IRIS.
Made with FlippingBook - Online catalogs