CROI 2019 Abstract eBook
253 EBV AND CMV LEVELS IN BLOOD ARE ASSOCIATED WITH NON-AIDS EVENTS DURING ART Sara Gianella 1 , Carlee Moser 2 , Andrej Vitomirov 1 , Ashley McKhann 2 , Laura Layman 1 , Brianna Scott 1 , Steven Lada 1 , Ronald Bosch 2 , Martin Hoenigl 1 , Nell Lurain 3 , Alan Landay 3 , Michael M. Lederman 4 , Peter W. Hunt 5 , Davey M. Smith 1 1 University of California San Diego, La Jolla, CA, USA, 2 Harvard University, Boston, MA, USA, 3 Rush University, Chicago, IL, USA, 4 Case Western Reserve University, Cleveland, OH, USA, 5 University of California San Francisco, San Francisco, CA, USA Background: Despite antiretroviral therapy (ART), HIV infection remains associated with higher morbidity/mortality, driven in part by increased inflammation. We sought to identify associations between cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) DNA in peripheral blood mononuclear cells (PBMC) with occurrence of non-AIDS events and mortality during ART. Methods: Participants (140 cases, 305 controls, 929 samples) were selected from the ACTG ALLRT trial; all were HIV suppressed on ART at year 1 and thereafter. Blood was collected: pre-ART (baseline), 1-year post-ART, and immediately pre-event (for cases). Cases included myocardial infaction/stroke, malignancy, serious bacterial infection or death. Controls had an event-free follow-up equal or greater than the relevant case. Participants were matched on age (within 10 years), sex, pre-ART CD4+ count (within 50 cells/mm3), ART regimen, and parent study. At each time-point, levels of CMV and EBV DNA were measured in PBMC by ddPCR. Levels of CMV and EBV IgG were measured at year 1 in plasma by ELISA. Other cellular and soluble biomarkers were obtained from previous projects (see table). Conditional logistic regression analysis assessed associations of the biomarkers with events, adjusted for relevant covariates. Correlation between biomarker levels were assessed with Spearman’s correlations among controls. Results: Cellular CMV DNA was detected in 25% of all time-points, while EBV was detected in >90%. Higher levels of EBV were associated with an increased risk of events at all time points (OR per one IQR = 1.5-1.7, all p<0.009), with the strongest associations at baseline. Associations remained unchanged when adjusting for relevant clinical factors. At year 1 (but not other timepoints), having detectable CMV DNA (yes/no) was associated with increased risk of events in most adjusted models (OR per one IQR = 1.4-1.8, p ranging 0.03-0.17). CMV and EBV levels were correlated only at the pre-event time point (r=0.18, p<0.0001). Levels of EBV DNA were associated with EBV IgG (r=0.37, p<0.0001), while CMV DNA was not associated with CMV IgG. Levels of CMV were correlated with all soluble markers at baseline, while EBV DNA was correlated with some biomarkers at each time point (see table). Conclusion: Subclinical replication of EBV and (to lesser extent) CMV in blood were associated with increased inflammation and were predictive of non-AIDS events and mortality in ART suppressed HIV-infection.
254 GAMMA DELTA T-CELL IR SIGNATURES REVEAL DIVERGENCE OF HEALTHY AND AVIREMIC HIV+ AGING Anna C. Belkina 1 , Alina Starchenko 2 , Katherine Drake 3 , Elizabeth Proctor 2 , Riley Pihl 1 , Alex J. Olson 1 , Douglas Lauffenburger 2 , Nina Lin 1 , Jennifer Snyder- Cappione 1 1 Boston University, Boston, MA, USA, 2 MIT, Cambridge, MA, USA, 3 Cytobank, Inc., Santa Clara, CA, USA Background: Even with effective viral control, HIV-infected individuals are at a higher risk for morbidities associated with older age than the general population, and these serious non-AIDS events (SNAEs) track with plasma inflammatory and coagulation markers. The cell subsets driving inflammation in aviremic HIV infection are not yet elucidated. Also, whether ART-suppressed HIV infection causes premature induction of the inflammatory events found in uninfected elderly or if a novel inflammatory network ensues when HIV and older age co-exist is unclear. Methods: In this study we measured combinational expression of five inhibitory receptors (IRs) on seven immune cell subsets and 16 plasma markers from peripheral blood mononuclear cells (PBMC) and plasma samples, respectively, from a HIV and Aging cohort comprised of ART-suppressed HIV-infected and uninfected controls stratified by age (≤35 or ≥50 years old). For data analysis, multiple multivariate computational algorithms (cluster identification, characterization, and regression (CITRUS), partial least squares regression (PLSR), and partial least squares-discriminant analysis (PLS-DA)) were used to determine if immune parameter disparities can distinguish the subject groups and to investigate if there is a cross-impact of aviremic HIV and age on immune signatures. Results: IR expression on gamma delta (γδ) T cells exclusively separated HIV+ subjects from controls in CITRUS analyses and secretion of inflammatory cytokines and cytotoxic mediators from γδ T cells tracked with TIGIT expression among HIV+ subjects. Also, plasma markers predicted the percentages of TIGIT+ γδ T cells in subjects with and without HIV in PSLR models, and a PLS-DA model of γδ T cell IR signatures and plasma markers significantly stratified all four of the subject groups (uninfected younger, uninfected older, HIV+ younger, and HIV+ older). Conclusion: These data implicate γδ T cells as an inflammatory driver in ART-suppressed HIV infection and provide evidence of distinct ‘inflamm-aging’ processes with and without ART-suppressed HIV. 255 SENESCENCE & EXHAUSTION OF T-CELL MEMORY SUBSETS INCREASED IN AGING PERSONS WITH HIV Jessica L. Castilho , Louise Barnett, Megan M. Turner, Joshua Simmons, Cindy Hager, Rita M. Smith, Beverly O. Woodward, Morgan Lima, Briana Furch, Mark Pilkinton, Timothy R. Sterling, Spyros Kalams Vanderbilt University, Nashville, TN, USA Background: Changes in adaptive immunity including activation, senescence, and exhaustion have been observed in aging and in HIV infection and have been associated with aging-related co-morbidities. We designed a prospective cohort study to examine the HIV- and aging-related changes of T lymphocytes among aging persons living with HIV (PLWH). Methods: We recruited adults aged 30-39 years and ≥50 years with and without HIV infection in Nashville, TN. PLWH must have had HIV-1 RNA <40 copies/mL ≥1 year. We collected demographic, social, health, and aging-related data on all persons. PMBCs were analyzed with flow cytometry to evaluate the frequency and phenotypes of CD4 and CD8 T cell memory populations (naïve [Tn],central memory [Tcm], effector memory [Tem], and effector memory RA+ [TemRA] cells) and expression of markers of activation (HLA-DR+CD38+), senescence (CD57+KLRG1+), and exhaustion (PD-1+). We used linear regression and Fisher exact tests to assess age- and HIV-infection related differences in T cell phenotypes. Results: Our baseline data of 80 persons includes 17 adults without HIV (10 aged 30-39 years, 7 aged ≥50 years) and 63 PLWH (19 aged 30-39 years, 44 aged ≥50 years). In all, 23%were women and 34%were African American; 59% of HIV-negative and 95% of PLWH were seropositive for CMV; and the median CD4 cell count of PLWH was 779 [interquartile range: 507, 938]). In general, increasing age was associated with decreased CD4 and CD8 naïve T cell populations in both HIV-negative persons and PLWH (PLWH CD4 Tn β=-0.58% per year of age, p=0.002; HIV-negative CD4 Tn β= -0.85%, p=0.007) and increasing proportions of CD8 Tem and TemRA in PLWH (β= 0.19% [p=0.050] and 0.29% [p=0.055], respectively). T cell activation was generally very
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