CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

613

Epigenetic Modifications Predictive of Cognitive Frailty in Cocaine-Using People Living With HIV Marianna Baum, Leonardo Acuna, Haley Fonseca, Manuel Barbieri, Raul Gonzalez Jr, Steven Black, Matthew Sutherland, David Brown, Paolo Chaves, Edgar Vieira, Francisco Fernadez Lima, Qingyun Liu, Samantha Gonzales, Xuexia Wang, Stephanie Gieseken Florida International University, Miami, FL, USA Background: People living with HIV (PLWH) are disproportionately burdened by neurocognitive impairment (NCI) and physical frailty. Cognitive frailty, the combination of both, results in poorer outcomes than physical frailty or NCI alone. While epigenetic modifications are linked to each of these conditions separately, cognitive frailty remains understudied, and HIV and cocaine use may worsen outcomes. We investigated epigenetic profiles to identify methylation patterns predictive of cognitive frailty in people living with and without HIV and cocaine use. Methods: We conducted a preliminary epigenome-wide association study (EWAS) with a subset of participants from the Miami Adult Studies on HIV (MASH) cohort. DNA samples from PBMCs of a random sample were stratified by HIV serostatus and cocaine use and analyzed using the Illumina MethylationEPIC_v-2-0 beadchip. HIV serostatus was confirmed with medical records and cocaine use with urine toxicology. Cognitive frailty was defined with the IANA/IAGG criteria, combining physical frailty (Fried criteria), and neurocognitive impairment (Mini Mental State Examination). Linear regression models examined associations between methylation patterns, cognitive frailty, HIV status, and cocaine use, adjusting for confounders. Significant CpG were identified with F test for the overall model (p< 0.01) and t-test for cognitive frailty (p<0.05). Results: Average age ( n =31) was 63.35 ±3.2SD, 100% were male, non-Hispanic Black, and 61.3% had a high school education or less. All were virally suppressed with an average CD4 cell count of 564.44±295.6SD. One CpG site (cg08287344) in EWAS had significant differential methylation patterns among the HIV/ COC groups associated with cognitive frailty ( p =2.64x10 -7 of F test; p =0.05 for cognitive frailty, p =3.52x10 -7 for HIV/COC). DNA methylation levels were lower in PLWH using cocaine who had cognitive frailty compared to HIV-negative participants not using cocaine and without cognitive frailty (Fig.1). Conclusions: PLWH with cocaine use and cognitive frailty show greater epigenetic dysregulation compared to HIV-negative counterparts who do not use cocaine. Lower DNA methylation levels indicate changes in gene expression related to inflammation, neurocognitive decline, or drug-related stress. This suggests cocaine use may exacerbate epigenetic effects of HIV, potentially contributing to worsening health and cognitive outcomes. Further research is needed to explore these mechanisms.

an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Methods: In primary human monocyte-derived macrophages (hMDM) and human induced pluripotent stem cell-derived microglia (iMg), changes in gene expression and cytokine/chemokine secretion following infection with 1 ng/mL HIV ADA were evaluated using RNA sequencing and Bio-Plex® 48-Plex Pro Human Cytokine Screening Panel, respectively. To mitigate the potential dual-receptor activity at both CB 1 and CB 2 , cultures were exposed to the CB 2 -specific JWH-133, a synthetic cannabinoid (Ki, 3.4 nM; >200-fold selectivity for CB 2 over CB 1 ) during the 24-h initial inoculation with HIV, and cultures were maintained for 9 days post-infection (DPI). To confirm that the observed effects were CB 2 -specific, SR-144,528, a CB 2 -selective inverse agonist (Ki, 0.6 nM; >600-fold selectivity for CB 2 over CB 1 ) was added 1 h prior to JWH-133 to ensure saturation of receptors. Results: JWH-133 reduced HIV replication in primary hMDM and iMg at differing doses and timepoints (~50% reduction on DPI7 with 10 µ M JWH-133 in hMDM, ~35% on DPI5 with 1 µ M JWH-133 in iMg); these effects were abrogated with SR-144,528 pretreatment. In both hMDM and iMg, the effect of JWH-133 corresponded to the basal expression level of CNR2 , which encodes CB 2 , and related endocannabinoid transcripts in each cell type. JWH-133 broadly reduced cytokine release from HIV-infected hMDM but not iMg. RNA-seq revealed that CB 2 agonism primarily altered interferon and integrated stress response pathways in hMDM while altering homeostatic pathways, including synapse maintenance and phagocytosis, in iMg. Further analyses in iMg revealed that NLRP3 inflammasome activation, but not priming, was reduced by CB 2 activation, which did not inhibit HIV-induced NF-kB activation. Conclusions: This study identifies key differences in CB 2 response between myeloid lineage cell types and implicates CB 2 -specific agonists as promising candidates for the regulation of HIV-associated neuroinflammation. Neuronal Injury in a Subset of PWH During Acute HIV Infection and Up to 5 Years After Immediate ART Phillip Chan 1 , Suteeraporn Pinyakorn 2 , Carlo Sacdalan 3 , Eugène Kroon 3 , Pathariya Promsena 3 , Donn Colby 2 , Somchai Sriplienchan 3 , Nittaya Phanuphak 4 , Sandhya Vasan 5 , Robert Paul 6 , Magnus Gisslén 7 , Henrik Zetterberg 7 , Victor Valcour 8 , Lydie Trautmann 5 , Serena Spudich 1 , for the RV254/SEARCH 010 Study Team 1 Yale University, New Haven, CT, USA, 2 US Military HIV Research Program, Bethesda, MD, USA, 3 SEARCH, Bangkok, Thailand, 4 Institute of HIV Research and Innovation, Bangkok, Thailand, 5 Henry M Jackson Foundation, Bethesda, MD, USA, 6 University of Missouri St Louis, St Louis, MO, USA, 7 Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, 8 University of California San Francisco, San Francisco, CA, USA Background: Neurofilament light chain (NFL) is a sensitive neuronal injury marker, with levels elevated in both neuroinflammatory and neurodegenerative diseases. Cerebrospinal fluid (CSF) NFL is elevated in up to 40% of people with HIV during the 1st year of infection and has been reported as normalizing after antiretroviral therapy (ART). We measured CSF NFL cross-sectionally during acute HIV infection (AHI) and at longitudinal time points up to 5 years after immediate initiation of ART in an observational study. Methods: RV254 AHI cohort participants completed optional lumbar punctures during pre-ART AHI (week 0, n=136) and at post-ART visits (weeks 24, 48, 96 & 240, n=201). All post-ART sample donors had plasma HIV RNA ≤50 cps/ml. RV254 participant CSF NFL measurements were compared to 44 people without HIV (PWoH), both adjusted to an age of 30 (see footnotes in Figure ), and also to age-based upper normal limits (UNL) based on published data. Chi-square test or non-parametric tests were used for statistical analysis. Results: Among the 136 week 0 CSF samples, 135 (99%) were from males, with median age of 27 (IQR 23-32) years. The median plasma and CSF HIV RNA were 5.99 (IQR 5.08-6.78) and 3.22 (IQR 1.91-4.24) log 10 cps/ml; median CD4+ T-cell counts were 379 (IQR 263-543) cells/mm 3 . At pre-ART week 0, RV254 participants had higher CSF NFL levels than PWoH (p<0.001, see Figure ), and also had a higher rate of abnormal CSF NFL (>age-based UNL) than PWoH (20 (15%) vs. 1 (2%), p=0.029). Among AHI at week 0, CSF NFL positively correlated with CSF HIV RNA (r=0.206, p=0.016), CD8+ T-cell (r=0.249, p=0.004) and negatively correlated with CD4/CD8 ratio (r=-0.242, p=0.005). During post-ART visits (ART initiation 20 (IQR 15-26) days of estimated infection), AHI CSF samples consistently showed higher NFL levels than controls (p<0.001), with 5/62 (8%) and 10/139 (7%) samples from week 24 and week 48 or later exceeding the age-based UNL. Only one CSF sample at week 24 and

Poster Abstracts

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614

Differential Effects of CB2 Agonism on HIV Replication and Inflammatory Activation in Myeloid Cells Alexander Starr 1 , Sara Rathore 2 , Marzieh Daniali 3 , Peter J. Gaskill 3 , Cagla Akay Espinoza 1 , Kelly L. Jordan-Sciutto 1 1 University of Pennsylvania, Philadelphia, PA, USA, 2 Boston University, Boston, MA, USA, 3 Drexel College of Medicine, Philadelphia, PA, USA Background: Evidence indicates that brain-resident myeloid cells, including perivascular macrophages and microglia, provide a reservoir for HIV infection in the central nervous system (CNS). Data also suggest that the inflammatory activity of these cells is associated with HIV-associated cognitive impairment. We investigated whether cannabinoid receptor (CB) 2 (CB 2 ),

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