CROI 2019 Abstract eBook
low and did not significantly differ by HIV status or age. Increasing age was associated with increased senescence in CD4 and CD8 memory subsets (Figure 1a) and with increased exhaustion in CD4 subpopulations (Figure 1b). Overall, aging-related changes were similar between HIV-negative persons and PLWH. T cell phenotypes were not statistically associated with frailty in HIV-negative persons or PLWH. Conclusion: Among PLWH with virologic suppression, increasing age was associated with loss of naïve T cells and increasing proportions of highly differentiated, exhausted and senescent memory T cells. Further research into the mechanisms and effects of aging-associated adaptive senescence and exhaustion in PLWH is needed.
[0-279], p=0.68). When compared to participants with no mutations, those with TET2 tended to have higher Agatston scores: 232[46-874], p=0.07, but after adjustment for age and sex, TET2 was no longer associated with coronary calcium: β=-0.04 [-0.19, 0.10]; p=0.57. Conclusion: CH is common among older treated HIV+ persons. Albeit limited by sample size, our analyses suggest that CH may be associated with dysregulated inflammation.
257 IMMUNOSENESCENCE IN HIV IS ASSOCIATED WITH CMV STATUS AND LOWER CD4:CD8 RATIO Tara McGinty 1 , Sarah Miles 1 , Willard Tinago 1 , Caroline Sabin 2 , Alan Landay 3 , Jeffrey Martinson 3 , Charlotte Prior 4 , Brenda Doak 4 , Cillian De Gascun 1 , Alan Macken 1 , Gerard Sheehan 4 , John Lambert 4 , Aoife G. Cotter 1 , Patrick W. Mallon 1 1 University College Dublin, Dublin, Ireland, 2 University College London, London, UK, 3 Rush University Medical Center, Chicago, IL, USA, 4 Mater Misericordiae University Hospital, Dublin, Ireland Background: It remains unclear whether increased immunosenescence observed in people living with HIV (PLWH) is driven by high rates of cytomegalovirus (CMV) co-infection or underlying immune dysfunction. We investigate relationships between immune function, CMV IgG positive status (CMV+) and immunosenescence in PLWH and HIV- control subjects. Methods: Using cryopreserved PBMC from subjects in HIV UPBEAT, a cohort of PLWH and HIV- controls from similar demographic backgrounds, we measured CD4 and CD8 T-cell immunosenescence by flow cytometry, defined as CD4+/ CD8+, CD28- CD57+ T-cells. We used linear regression to explore associations between immunosenescence, HIV status, demographics, CMV+, CMV IgG titres and CD4:CD8 ratio. Data are median (interquartile range) or model estimate (ME) [95% confidence interval (CI)] unless stated. Results: Of 219 subjects, 107 (48.8%) were PLWH (68%male, 34% African, age 47 [39-53] years, 30% smokers) and 112 were HIV- (48%male, 17% African, age 50 [44-56] years, 15% smokers). PLWH had lower CD4:CD8 ratios (0.89 [0.65-1.19] vs 2.3 [1.63-3.18], P<0.001), higher % of senescent CD4+ and CD8+ T-cells (4.2 [1.4-7.6] vs 0.5 [0.1-2.1] and 34 [21.0-45.4] vs 22.6 [14.4-35.0] respectively, both P<0.001) and were more likely to be CMV+ (89% v 40%, P<0.001). In univariate analyses, HIV status, lower CD4:CD8 ratio and CMV+ were associated with higher CD4+ and CD8+ senescence. In analyses adjusted for age, gender, ethnicity and smoking, HIV infection remained significantly associated with higher CD4+ (ME [95%CI) 1.668 [1.168-2.168], P<0.001) and CD8+ (0.306 [0.115-0.497], P=0.002) T-cell senescence. Additional adjustment for CD4:CD8 ratio or CMV+ attenuated this association (table1), with both lower CD4:CD8 ratio and CMV+ associated with increased CD4+ and CD8+ senescence. When both were included in the model, CD4:CD8 ratio and CMV+ remained independently associated with increased T-cell senescence. CMV+ was similarly associated with CD4+ and CD8+ senescence in PLWH and HIV- subjects (interaction p=0.27 for each) but associations with CD4:CD8 ratio were slightly weaker among PLWH (interaction p=0.002 and p=0.001, respectively). Replacing CMV+ with CMV IgG titres did not alter these findings. Conclusion: Increased CD4+ and CD8+ senescence in PLWH can be attributed to both immune dysfunction, reflected in lower CD4:CD8 ratios, and CMV status. Future research should focus on immunosenescence and its impact on clinical outcomes in PLWH.
256 CLONAL HEMATOPOIESIS AMONG OLDER TREATED HIV+ PERSONS ENROLLED IN COCOMO Álvaro H. Borges 1 , Christian H. Eskelund 1 , Rebekka F. Thudium 1 , Yanan Zhao 1 , Andreas D. Knudsen 1 , Marco Gelpi 1 , Cavan Reilly 2 , James Pankow 2 , Mark Polizzotto 3 , Franceso Favero 1 , Sisse R. Ostrowski 1 , Klaus F. Kofoed 1 , Joachim Weischenfeldt 1 , Kirsten Grønbæk 1 , Susanne D. Nielsen 1 , for the COCOMO 1 Rigshospitalet, Copenhagen, Denmark, 2 University of Minnesota, Minneapolis, MN, USA, 3 Kirby Institute, Sydney, NSW, Australia Background: Clonal hematopoiesis (CH) is the expansion of blood cell subpopulations containing somatic mutations. CH increases with age and has been associated with death, cancer and cardiovascular disease in the general population. Here, we set out to investigate CH prevalence and its association with inflammation, T cell subpopulations and coronary calcium among older treated HIV+ persons enrolled in the COCOMO cohort. Methods: Targeted error-corrected sequencing of 21 CH-associated genes was performed in stored buffy coats of COCOMO participants older than 55y. IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17A, IFNγ and TNFα levels were measured in plasma using a multiplex assay. Flow cytometry identified T cell subpopulations. Agatston score was used to quantify coronary artery calcification among those participants undergoing a cardiac CT. Cytokine levels, T cell subpopulations and Agatston score were compared between participants with ad without CH. Multivariate logistic/linear regression identified independent associations. Results: Out of 190 participants (median [IQR] age: 66y [61-70], 87%male, mean CD4+ cell count 678, 99.5% virologically suppressed), 49 (25.8%) had at least one mutation. In line with reports from general population, the most frequent mutations (n/%) were: DNMT3A (25/13.2), TET2 (12/6.3) and ASXL1 (8/4.2) (Figure). Those with any mutation were older (68 [60-76] vs. 65 [57-73], p=0.009) and more likely to be male (98 vs. 83%, p=0.006). No differences were observed in terms of HIV-related factors. Participants with CH had lower IL-10 levels (0.51 [0.29-0.69] vs. 0.58 [0.36-0.89]pg/mL, p=0.049) and tended to have a higher proportion of detectable IL-4 levels (48.5 vs 25.9%, p=0.09); other cytokine levels were similar. With adjustment for age and sex, CH remained associated with lower IL-10 (adjusted β [95%CI]: -0.10 [-0.20, -0.01], p= 0.03). Participants with and without CH had similar proportions of T cell subpopulations (p>0.10 for all subpopulations investigated). Participants with and without CH had similar median Agatston scores (111 [5-357] vs. 76
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