CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

319 Association Between sCD163 and CMV IgG in Virologically Suppressed HIV+ Patients Aimee Hodowanec 1 ; BrettWilliams 1 ; Barbara Hanson 1 ; Britt Livak 2 ; Sheila Keating 3 ; Nell Lurain 1 ; Oluwatoyin M. Adeyemi 4 1 Rush University Medical Center, Chicago, IL, US; 2 University of Chicago, Chicago, IL, US; 3 Blood Systems Research Institute/University of California San Francisco, San Francisco, CA, US; 4 Ruth M Rothstein CORE Center, Chicago, IL, US Background: HIV+ patients with controlled viremia have ongoing chronic inflammation which has been associated with an increased risk for cardiovascular and neurocognitive disease. Cytomegalovirus (CMV) has been implicated as a potential driver of this inflammation. Soluble CD163 (sCD163) is a marker of monocyte/macrophage activation and is upregulated in inflammatory states. We explore the relationship between CMV and sCD163 in HIV+ pts with well controlled viremia. Methods: Patient samples and data from existing cohorts of HIV+ subjects with undetectable HIV RNA were utilized for this study. Specimens were collected between 2009 and 2013. ELISA was used to measure sCD163 level in plasma and CMV immunoglobulin G (IgG) level in serum. All subjects underwent plasma CMV PCR testing. Bivariate analysis (Pearson Correlation and Kruskal Wallis Test) and multivariate linear regression analysis were performed to identify variables associated with CMV IgG level. Variables included in the multivariate model are sex, race, age, duration of antiretroviral use, and sCD163 level. Results: Of 139 adult, virologically suppressed HIV+ subjects, 130 (94%) were CMV seropositive and were included in our analysis. The median age was 55 (51-59) years, 63% male, 61% black, 18% Hispanic, 12%white, and 2% other race. The median CD4 count was 512 (193-696) cells/mm 3 , median sCD163 was 1171.3 ng/mL (886.7-1554.1), and median CMV IgG level was 39.0 IU/mL (32.0-46.0) (results reported as median (IQR) unless stated otherwise). No subjects had detectable plasma CMV DNA. Bivariate analysis revealed a significant, positive correlation between sCD163 and CMV IgG levels (r = 0.19, p = 0.03) and a trend towards increased CMV IgG among those with coronary disease (H = 2.99, p = 0.08). Multivariate analysis also identified a positive relationship between CMV IgG levels and sCD163 (coef. 0.004; 95%CI 0.001-0.003 p = 0.01). Conclusions: Among HIV+ adults with undetectable HIV RNA, increased CMV IgG level (even in the absence of CMV viremia) is associated with increased sCD163 level. Our finding adds to the body of evidence suggesting that CMV is involved in the complex pathophysiology of chronic inflammation in HIV. Cellular correlates of these elevated CMV IgG levels deserve further exploration. 2:30 pm– 4:00 pm Manipulating Immune Activation 320 The mTORC1 Inhibitors, Temsirolimus and Everolimus, Suppress HIV Patient-Derived CD4+ T-Cell Death and Activation In Vitro Clovis S. Palmer 1 ; Matias Ostrowski 4 ; Jingling Zhou 1 ; Linda Lam 1 ; Alan Landay 2 ; Anthony Jaworowski 1 ; Joseph M. McCune 3 ; Suzanne M. Crowe 1 1 Burnet Institute, Melbourne, Australia; 2 Rush University Medical Center, Chicago, IL, US; 3 University of California San Francisco, San Francisco, CA, US; 4 Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Buenos Aires, Argentina Background: Activated T cells support their energetic and biosynthetic demands in part by increasing glucose uptake and glycolysis. Glucose transporter 1 (Glut1), the major glucose transporter on T cells, is essential for CD4+ T cell activation and effector functions, and its expression is increased on CD4+ T cells in HIV-infected subjects. High Glut1 expression on CD4+ T cells is associated with immune activation/inflammation and low CD4 cell count, irrespective of treatment status. We hypothesized that experimental inhibition of glycolysis in activated CD4+ T cells would inhibit HIV-induced cell death and supress the production of inflammatory mediators. Methods: Flow cytometry was used to examine Glut1 expression on CD4+ T cells from 58 virologically supressed HIV+males (viral load <50 RNA copies/ml), 40 immunological responders (median CD4: 700), 18 immunological non-responders (median CD4: 246), and 29 HIV- male controls. Glut1-expressing CD4+ T cells (CD4 Glut1 ) were sorted on a FACSAria machine. Glycolytic inhibition was achieved using the mTORC1 inhibitors, temsirolimus or everolimus. Cell death was measured by a trypan blue exclusion. Secreted L-lactate levels served as a measure of glycolytic activity and cytokine levels were determined by ELISA. Results: The proportion of CD4 Glut1 cells was significantly elevated in immunological non-responders (median: 14.8, IQR: 11.7-36.9, p<0.0001) compared to responders (median: 8.4, IQR: 5.4-12.3) and HIV- controls (median: 4.9, IQR: 1.6-6.9, p<0.0001). CD4 Glut1 cells purified from HIV+/ART subjects underwent more rapid cell death in culture compared to CD4+ T cells not expressing Glut1. The in vitro death of both CD4+ T cell populations was markedly reduced when co-cultured with non-toxic concentrations of the temsirolimus or everolimus. Remarkably, both drugs at a concentration as low as 1 nM effectively suppressed glycolysis by 25-50% in CD4+ T cells that were activated in vitro with PMA and IL-2, with effects persisting beyond 7 days after exposure. Further, temsirolimus suppressed CD4+ T cell activation (as measured by HLA-DR expression) and TNF secretion by approximately 20 and 75%, respectively. Conclusions: High glycolytic metabolismmay be associated with accelerated CD4+ T cell death in HIV+ persons. These data suggest that periodic addition of the clinically safe mTORC1 inhibitors, temsirolimus or everolimus, to current ART regimen may reduce residual T cell activation and inflammation, and improve T cell recovery. 321 Decreased Monocyte ActivationWith Daily Acyclovir Use in HIV-1/HSV-2 CoinfectedWomen Andrew D. Redd 1 ; Kevin Newell 2 ; Eshan U. Patel 1 ; Fred Nalugoda 3 ; Paschal Ssebbowa 3 ; Sarah Kaliballa 3 ; Ronald H. Gray 4 ;Thomas C. Quinn 1 ; David Serwadda 5 ; Steven J. Reynolds 1 1 National Institute of Allergy and Infectious Diseases (NIAID), Washington, DC, US; 2 Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, US; 3 Rakai Health Sciences Program, Kalisizo, Uganda; 4 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US; 5 Makerere University College of Health Sciences, Kampala, Uganda Background: In two separate randomized control trials, acyclovir treatment of HSV-2/HIV coinfected individuals significantly reduced HIV viral load, and decreased the rate of disease progression. It is unclear if the protective effect of acyclovir use on HIV disease is a direct effect of decreasing HIV replication, or a secondary effect of decreased immune activation associated with less herpetic reactivation. Methods: HIV-1/HSV-2 co-infected women from the Rakai Health Sciences Program, Uganda were enrolled in a double-blind randomized placebo-controlled trial to examine the effect of daily acyclovir use on HIV disease progression. Serum samples were collected at enrollment and every six months for two years (n=301). High sensitivity CRP and sCD14 levels were measured on all available serum samples. Longitudinal analyses of treatment outcome were right-censored at initiation of HAART for those women who started therapy. The predictive value of CRP and sCD14 on survival was estimated using Kaplan-Meier survival curves and Cox proportional hazard regression models. Mixed-effects models were used to examine time varying CRP and sCD14 levels by study arm. WEDNESDAY, FEBRUARY 25, 2015 Session P-C11 Poster Session Poster Hall

Poster Abstracts

257

CROI 2015