CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

week 72 in participants who stopped telmisartan and continued ART only. We found that only 5.46% of DML identified at week 72 overlapped with changes observed at week 48. Conclusion: Telmisartan initiated during AHI affects epigenetic states of genes related to inflammation, immune response, and cellular proliferation in CSF cells. Telmisartan's effects on long-term epigenetic reprogramming of CNS cells and CNS outcomes warrant further investigation.

largest gene expression changes in PWH, including upregulation of pathways related to cytokine signaling and innate immunity. On the other hand, many genes were significant on DE analysis (p ≤.05) across all regions (151 PWH, 55 CTR) and multiple cell types (567 PWH, 974 CTR). For example, SERPINA3 was differentially expressed in PWH in INS, VST, and PFC by astrocytes, endothelial cells, neuronal cells, oligodendrocyte precursor cells, oligodendrocytes, microglia, and pericytes. Despite these widespread trends, 562 of the top 1000 significant results were genes differentially expressed in INS. Conclusion: We identified patterns of differential cell type abundance and gene/pathway expression in PWH. While our findings are consistent with previous single cell observations of glial cell involvement in PWH, our results indicate that many other cell types are affected by HIV and implicates the INS as a significant region for future exploration.

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Monocyte Epigenetic Age Relates to Non-Somatic Depressive Symptoms in Women With Undetectable HIV Kalen J Petersen 1 , Nicole Perez 2 , Ke Xu 3 , Yanxun Xu 4 , Lang Lang 4 , Kathryn Anastos 5 , Maria L. Alcaide 6 , Mardge H. Cohen 7 , Sadeep Shrestha 8 , Andrew Edmonds 9 , Jacquelyn Meyers 10 , Seble Kassaye 11 , Beau Ances 1 , Brad Aouizerat 2 , Leah H. Rubin 12 1 Washington University in St Louis, St Louis, MO, USA, 2 New York University, New York, NY, USA, 3 Yale University, New Haven, CT, USA, 4 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 5 Albert Einstein College of Medicine, Bronx, NY, USA, 6 University of Miami, Miami, FL, USA, 7 John H Stroger Jr Hospital of Cook County, Chicago, IL, USA, 8 University of Alabama at Birmingham, Birmingham, AL, USA, 9 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 10 State University of New York Downstate Medical Center Downstate Medical Center, Brooklyn, NY, USA, 11 Georgetown University, Washington, DC, USA, 12 The Johns Hopkins University, Baltimore, MD, USA Background: HIV and its neuropsychiatric complications have been linked with accelerated biological aging using several DNA methylation-based epigenetic clocks. Monocytes, which are essential to the innate immune response, may contribute to this biological aging effect. A recently developed epigenetic clock derived from monocytes showed acceleration in people with HIV who were heavy alcohol users. However, its relationship with depression is unknown. As depression disproportionately affects women, we examine epigenetic clocks as biomarkers of depressive symptomatology in women with HIV (WWH) and women without HIV (WWoH). Specifically, we focus on the link between epigenetic age and dimensions of depression (non-somatic [affective or cognitive] vs. somatic [sleep or appetite]) as the phenotypic expression of depression is heterogeneous. Methods: DNA methylation data and Center for Epidemiological Studies Depression Scale (CES-D) scores were available from 440 Women's Interagency HIV Study participants. Illumina MethylationEPIC microarrays were used to measure methylation levels in bisulfite-converted DNA from whole blood. Two estimates of biological age were calculated (Horvath age and monocyte age). Chronological age, Horvath age, and monocyte age were orthogonalized due to high mutual correlations. CES-D scores were used to quantify somatic and non-somatic depressive symptoms. In the full cohort (WWH+WWoH) and separately in WWH and WWoH, we used multiple linear regression to measure links between chronological or epigenetic age and depressive symptoms after confounder adjustment. Results: We included 261 WWH (chronological age=43.7±8.9 years; 38% Black; 48% Hispanic; 84% undetectable viral load) and 179 WWoH (age=39.5±10.0; 31% Black; 49% Hispanic). In the full cohort, monocyte age was significantly associated with non-somatic depressive symptoms (P=0.003; Fig. 1), particularly CES-D items reflecting anhedonia (P's=0.01). This pattern was driven by WWH with undetectable viral load (depressive non-somatic: P=0.047; CES-D anhedonia items: P's<0.05). Horvath age was not associated with non-somatic depressive symptoms. Neither monocyte age nor Horvath age were associated with somatic depression. Conclusion: Biological clocks reflecting the epigenetic age of immune cells may represent sensitive biomarkers of non-somatic depression in WWH. The relationship between morbidity and mortality-tuned epigenetic clocks (e.g.,

Poster Abstracts

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Epigenetic Impact in CSF Cells From 48 Weeks of Adjunctive Telmisartan in Acute HIV Michael J Corley 1 , Phillip Chan 2 , Eugene Kroon 3 , Napapon Sailasuta 4 , Alina P. Pang 1 , Nittaya Phanuphak 3 , Jennifer Chiarella 2 , Sandhya Vasan 5 , Robert Paul 6 , Lydie Trautmann 5 , Serena S. Spudich 2 , Lishomwa Ndhlovu 1 , for the SEARCH018/ RV408 Study Group 1 Weill Cornell Medicine, New York, NY, USA, 2 Yale University, New Haven, CT, USA, 3 SEARCH, Bangkok, Thailand, 4 University of Hawaii at Manoa, Honolulu, HI, USA, 5 Henry M Jackson Foundation, Bethesda, MD, USA, 6 University of Missouri St Louis, St Louis, MO, USA Background: Telmisartan, an angiotensin II receptor antagonist, is known to reduce inflammation. In a randomized trial, we examined whether 48 weeks of sustained adjunctive telmisartan initiated with antiretroviral therapy (ART) in acute HIV infection (AHI) would modify HIV's impact on the central nervous system (CNS). While we observed no significant changes in soluble makers of CNS inflammation or injury markers due to telmisartan, we did not evaluate its effects on CNS cells. Hence, we investigated whether telmisartan modified epigenetic states in cerebrospinal fluid (CSF) cells. Methods: We utilized a new ultra-low DNA input assay to measure genome wide DNA methylation (DNAm) epigenetic profiles in CSF cells at 48 and 72 weeks from 21 participants with AHI that were randomized 2:1 to initiate treatment with ART +/- telmisartan for 48 weeks. We used R statistical software to analyze DNA methylation data and identify differentially methylated loci using a linear model with FDR correction. Results: The median age of participants was 29 years (IQR: 24-34), pre-ART median log 10 plasma viral load was 5.95 copies/mL (5.36-6.48), pre-ART median CSF HIV RNA was 2.82 copies/mL (2.17-4.36), and pre-ART CD4+ T Cell count was 479 cells/mm 3 (95-688). Age, Fiebig stage, pre-ART plasma and CSF viral loads, and pre-ART CD4+ T cell count did not significantly differ between participants randomly assigned to ART+ telmisartan versus ART only groups. Comparing the DNAm states of CSF cells at Week 48 in participants receiving 48 weeks of ART+telmisartan versus ART, we identified 11,433 differentially methylated loci (DML) at a mean difference in DNAm of 10% or greater. Notably, DNAm levels of marker of proliferation Ki-67 MKI67, inflammatory gene IL1B, immune checkpoint receptor gene LAG3, central regulator of stress response gene CRH, and interferon stimulated gene IFI27 were significantly altered in CSF cells of participants receiving ART+ telmisartan versus ART only for 48 weeks. We examined the durability of telmisartan-associated changes in CSF cells at

PhenoAge and GrimAge) and depression merits future study. The figure, table, or graphic for this abstract has been removed.

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