CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

866

ART Exposure and Accelerated Aging in PLHIV: Insights From Proteomic and Methylation Clocks Nadira Vadaq 1 , Victoria Rios Vazquez 1 , Louise E. van Eekeren 1 , Adriana Navas 1 , Jéssica dos Santos 1 , Wilhelm A. Vos 2 , Albert L. Groenendijk 3 , Marc J. T. Blaauw 4 , Erni Nelwan 5 , Leo Joosten 1 , Jan van Lunzen 1 , Cheng-Jian Xu 6 , Vasiliki Matzaraki 1 , Andre van der Ven 1 , Mihai G. Netea 1 , for the 2000HIV Human Functional Genomics Partnership Program 1 Radboud University Medical Center, Nijmegen, Netherlands, 2 OLVG, Amsterdam, Netherlands, 3 Erasmus University Medical Center, Rotterdam, Netherlands, 4 Elisabeth-TweeSteden Ziekenhuis, Tilburg, Netherlands, 5 University of Indonesia, Jakarta, Indonesia, 6 Hannover Medical School, Hannover, Germany Background: People living with HIV (PLHIV) using antiretroviral therapy (ART) are exposed to persistent low grade of inflammation, which may accelerate aging. However, the impact of various ART regimens on residual inflammation and accelerated aging remains largely unclear. This study investigates the relationship between cumulative ART exposure and age acceleration in virally suppressed PLHIV on ART. Methods: Data from 1,875 PLHIV in the 2000HIV cohort (NCT03994835) were used to analyze cumulative ART exposure (in years), categorized by regimen and drug class, with detailed treatment data available for each participant. Age acceleration was assessed using biological clocks based on targeted proteomics (proteomic clock) and genome-wide methylation data (epigenetic clocks: Horvath, Hannum, PhenoAge, and GrimAge). Plasma protein levels (n=3072) were measured via proximity extension assay, and genome-wide DNA methylation was profiled using the Illumina MethylationEPIC array. We first examined the relationship between cumulative ART exposure and age advancement score using five biological clocks. We then performed differential expression analyses (DEA) and pathway enrichment analyses of proteomic data to elucidate underlying mechanisms. Results: Proteomic and methylation clocks were strongly correlated. Participants aged 36–60 showed faster epigenetics age acceleration compared to both younger (18–35) and older (60+) participants (P<0.05). Longer cumulative exposure to dolutegravir (DTG), rilpivirine (RPV) and nelfinavir (NFV) was associated with lower age advancement scores on at least a biological clock. In contrast, longer exposure to tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), darunavir (DRV), atazanavir (ATV), and dideoxynucleoside analogues (d-drugs) was related to higher age advancement scores (Figure 1; P<0.05, adjusted for chronological age). The effect of cumulative drug exposure on proteomic and methylation clocks was largely consistent. In participants exposed to DTG and RPV, DEA revealed significant downregulation of innate immune pathways, including cytokine and chemokine response, apoptotic process, and neutrophil chemotaxis, while exposure to DRV, ATV was associated with upregulation of these pathways. Conclusions: Cumulative ART exposure influences age acceleration in PLHIV, with distinct effects across regimens and drug classes. Innate immune pathways appear to be key drivers of these effects and are promising therapeutic targets to mitigate accelerated aging.

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Epigenetic Age Acceleration and CD4/CD8 Ratio in People With Well-Controlled HIV Infection Alejandro de Gea Grela 1 , Andrés Esteban-Cantos 2 , Francisco Jurado 3 , Lucía Gutiérrez 1 , Patricia Martínez-Martín 2 , Cristina Marcelo 1 , Juan Carlos González 1 , María Jiménez-González 1 , Alejandro Díez-Vidal 1 , María del Mar Arcos-Rueda 2 , Luis Ramos 2 , Juan Miguel Castro 1 , Berta Rodés 1 , Jose R. Arribas 1 , Rocío Montejano Sanchez 2 1 Hospital La Paz Institute for Health Research, Madrid, Spain, 2 Hospital Universitario La Paz, Madrid, Spain, 3 Centro Nacional de Investigaciones Oncológicas, Madrid, Spain Background: In people with HIV infection (PWH), epigenetic age acceleration (EAA) markers are associated with physiologic frailty and mortality. However, the relationship between these epigenetic biomarkers and the CD4/CD8 ratio, another key prognostic marker in people with well controlled HIV infection, remains unexplored. Methods: Cross-sectional study of long term aviremic PWH. Whole blood DNA methylation was assessed using the Illumina Infinium Methylation EPIC BeadChip microarray. We evaluated 5 epigenetic clocks (Horvath and Hannum’s clocks, PhenoAge, GrimAge and SkinBlood clock) and the DNA methylation based estimator of telomere length (DNAmTL). EAA was calculated as the residuals from the regression of epigenetic age on chronological age. We defined a low CD4/CD8 ratio as ≤0.5 and compared EAA with ratios below or above this cutoff. Multivariate linear and logistic regression models were employed to assess the association between CD4/CD8 ratio and EAA. Results: 62 participants with a median CD4/CD8 ratio of 0.39 (n=45; IQR: 0.3–0.44) in the CD4/CD8 ≤ 0.5 group and 1.32 (IQR: 0.68–1.67) in the CD4/ CD8 > 0.5 group were included. They were predominantly male (79%), with a median age of 57.9 years (IQR: 51.8-63), time since HIV diagnosis of 24.5 years (IQR: 15.8-30.2) and duration of viral suppression of 17 years (IQR: 10-21). Both groups were balanced in terms of age, body mass index, alcohol and tobacco intake, HIV transmission route, antiretroviral regimen and viral suppression time. However, those with a CD4/CD8 ratio ≤ 0.5 showed a significantly lower CD4+ cells nadir and shorter delay until ART initiation. Participants with a CD4/CD8 ratio ≤0.5 have significantly lower EAA-DNAmTL (p=0.036), indicating telomere shortening (Figure 1, Panel A), and a trend to higher EAA in the Hannum clock (p=0.088). No significant differences were observed in EAA measured by other epigenetic clocks, such as Horvath, PhenoAge, SkinBlood or GrimAge. In an adjusted linear regression model, EAA DNAmTL was positively associated with the CD4/CD8 ratio (p < 0.01) (Figure 1, Panel B), while AIDS diagnosis showed a marginal negative trend (p = 0.079). Other covariates were not significant. Conclusions: A lower CD4/CD8 ratio was associated with accelerated epigenetic aging measured by DNAmTL, indicating telomere shortening, but not with other epigenetic clocks. This suggests that DNAmTL may capture specific aspects of immune aging not reflected by other clocks. The figure, table, or graphic for this abstract has been removed. Inflammatory Markers and Frailty, Cognitive Impairment, Clinical Outcomes, and Mortality in PWH Win Min Han 1 , Kunling Wu 2 , Katherine Tassiopoulos 2 , Kate Ailstock 3 , Morgan Cummings 4 , Stephen Kerr 5 , Anchalee Avihingsanon 6 , Ponego Ponatshego 7 , Mosepele Mosepele 7 , Netanya Utay 8 , Nicholas Funderburg 3 , Kristine M. Erlandson 9 , for the ACTG A5322 (HAILO) Study Team 1 Kirby Institute, Sydney, Australia, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 Ohio State University, Columbus, OH, USA, 4 The Ohio State University, Columbus, OH, USA, 5 Chulalongkorn University, Bangkok, Thailand, 6 HIV-NAT, Thai Red Cross AIDS and Infectious Disease Research Centre, Bangkok, Thailand, 7 Botswana Harvard AIDS Institute Partnership, Gabarone, Botswana, 8 University of Texas Southwestern Medical Center, Dallas, TX, USA, 9 University of Colorado Anschutz Medical Campus, Aurora, CO, USA Background: The associations among inflammatory markers and prevalent or incident frailty, cognitive impairment (CI), clinical events and all-cause mortality in older people with HIV are poorly understood. Methods: Participants from the HAILO study ≥50 years were included. Frailty was evaluated using the Fried Frailty assessment (4-meter walk speed, grip strength, unintentional weight loss, exhaustion, low activity) and CI with the Neuroscreen (Trail Making A, Trail Making B, and Digit Symbol and Hopkins Verbal Learning Test). Included clinical events combined non-AIDS defining cancers, diabetes and cardiovascular, liver and kidney diseases. Baseline inflammatory markers included hsCRP, TNFR1, IL-6, CXCL-9 and inflammatory

Poster Abstracts

868

CROI 2025 266