CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

cognitive decline in Alzheimer's Disease. In animal models, TCR affects neuronal plasticity and memory through T helper 2-mediated responses. By disrupting immune homeostasis, HIV can affect TCR and cognition. We assessed whether TCR is involved in cognitive performance among PWH. Methods: Bulk TCR sequencing (IMMUNOVerse TCR) and cell-associated HIV DNA (ddPCR) were performed on samples from 5 central nervous system (CNS) regions (basal ganglia BG, occipital cortex OC, frontal motor cortex FC, hippocampus HC, thoracic spinal cord SC) and peripheral blood mononuclear cells collected ≤6 hours post-mortem from 9 PWH enrolled in the Last Gift cohort. TCR data were analyzed using MIXCR for richness, diversity, and clonality. Cognitive function was assessed within a year of death. Associations between TCR, cognition, and HIV DNA were explored through generalized linear models adjusted for age, HIV RNA, CD4 + count and nadir. Bonferroni correction was applied. Results: Participants were aged 65±8 years, with median CD4 + count 330 cells/ µ L, and 8/9 were white, male, with plasma HIV RNA<40 cp/mL. Cognitive assessment occurred within a median of 5 months of death. While HIV DNA and TCR richness/diversity did not differ across CNS regions, TCR clonality did (p=0.038): the highest clonality in SC and PBMCs and the lowest in FC. HIV DNA levels were not associated with TCR characteristics. Higher TCR richness/ diversity in FC, HC, OC, and SC was linked to poorer performance in learning, verbal, executive, and motor domains (adj.p<0.01 all). Higher TCR clonality in HC was associated with worse executive function (adj.p<0.01; Fig.1 ). No associations were found between TCR in the blood and cognitive performance. Higher HIV DNA correlated with slower processing speed (BG, HC, and OC) and poorer verbal function (HC), but also with improved executive and motor functions (FC, OC, and SC; Fig.1 ). Removing the single participant with detectable HIV RNA did not change the findings. Conclusions: This is the first evidence of an interaction between TCR in the CNS and cognitive performance in PWH. The absence of associations between HIV reservoir and TCR, along with the different relationships of TCR and HIV DNA with cognition highlight the complexity of the CNS viroimmune environment and suggest drivers other than HIV behind the link of TCR with cognition (e.g., co-infections).

of neurodegenerative disorders. We hypothesized that the application of this system would allow us to determine potentially dysregulated genes in iNs derived from PWH compared to persons without HIV (PWOH). Methods: Primary dermal fibroblasts were obtained from six PWH on suppressive cART (median age 53 years (range: 27 – 64); 83% Male; 50% White) and seven demographically matched PWOH (median age 55 years (range: 27 – 66); 71% Male; 57% White). Participant fibroblasts were transduced with two lentiviral vectors for the doxycycline-dependent expression of neuronal pioneer transcription factors NGN2, and ASCL1. Transdifferentiation into iNs was accomplished by treatment with doxycycline and a cocktail of small molecules. At day 21, live iNs were isolated by FACS sorting based on the neuronal marker PSA-NCAM. Neuronal identity was validated by immunocytochemistry and scRNA analysis. Bulk-RNAseq was performed to compare gene expression between iNs from PWH vs. PWOH. Results: Transcriptomic analysis identified 29 (p-adj. < 0.05, log2fc ± 0.5) differentially expressed genes between iNs derived from PWH and PWOH. Of these, 16 genes were downregulated and 13 upregulated in PWH iNs (Fig 1). Protein-protein interaction network mapping suggests PWH iNs exhibit differences in extracellular matrix organization and synaptic transmission. Amongst our findings, IFI27 has previously been shown to be upregulated in the post-mortem brain samples of PWH compared to PWOH. In contrast is our novel finding that expression of the FOXL2NB-FOXL2-LINC01391 genome locus is reduced in PWH iNs and associated with the degree of NCI in the PWH cohort (p<0.05). Conclusions: We have identified an iN gene signature of HIV through direct reprogramming of skin fibroblasts into neurons. Comprising 29 DEGs, this signature supports previous findings of HIV-1-related neuroinflammation while revealing additional, potentially novel mechanisms of NCI in PWH. The figure, table, or graphic for this abstract has been removed. Cerebrospinal Fluid Proteomic Patterns Vary With Neurobehavioral Characteristics Scott L. Letendre 1 , Bin Tang 1 , Mattia Trunfio 1 , Donald R. Franklin 2 , Michael Potter 2 , Melanie Crescini 2 , Jennifer Iudicello 2 , Robert K. Heaton 1 , Ronald Ellis 2 , Patricia K. Riggs 2 1 University of California San Diego, La Jolla, CA, USA, 2 University of California San Diego Medical Center, La Jolla, CA, USA Background: Current classification methods of neurobehavioral (NB) disorders in people with HIV (PWH) do not reflect their underlying biology well. We compared cerebrospinal fluid (CSF) proteomics between current classification methods and novel, multidimensional NB phenotypes (NBPs) to determine their biological associations. Methods: We assayed CSF from 286 virally suppressed participants with the Olink Target-96 Inflammation panel. 32 proteins had >75% of values below detection and were excluded. NB measures included global and domain deficit scores (GDS and DDS), Beck Depression Inventory (BDI)-II and subscales, and four NBPs derived from these features along with cognitive symptoms and daily functioning. NBP1: healthy, NBP2: depression-dominant, NBP3: unhealthy in all features, and NBP4: cognitive impairment-dominant. Analysis methods included linear regression, multiple testing correction (Benjamini-Hochberg), analysis of variance, Tukey highly significant difference test, and enrichment analysis such as pathway analysis. Results: Cohort characteristics: mean age 45 years, 21% female sex, 46.5% Black, median CD4+ T-cells 473/ µ L. 44 proteins associated with at least 1 NB measure, with some in common and others distinct (the Figure shows a subset of 7). CD40 and MMP-10 were the most common across all measures. Recall and motor domains (but not others) associated with multiple proteins, while GDS associated with fewer. BDI-II affective subscale associated with 32 proteins, the most of all NB measures, and apathy with fewer. Total BDI-II and other subscales did not associate with any protein. Each NBP associated with at least one unique protein compared to the healthy NBP. NBP3 was the most distinct. Biological process ontology analysis identified T-cell activation, chemotaxis, and B-cell and monocyte activation as the most represented. Conclusions: Cross-sectional analyses identified distinct profiles of CSF inflammation-related proteins for different NB characteristics. Overall, the most common biological pathways support the importance of persistent immune activation and migration across vascular barriers. Traditional composite variables (e.g., GDS, total BDI-II) had limited associations with inflammation,

Poster Abstracts

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A Transcriptional Signature of Induced Neurons Differentiates PWH on cART From People Without HIV Philipp N. Ostermann 1 , Youjun Wu 2 , Scott A. Bowler 1 , Mohammad A. Siddiqui 3 , Alberto Herrera 1 , Mega Sidharta 2 , Kiran Ramnarine 2 , Samuel Martínez-Meza 1 , Leslie Ann St Bernard 1 , Douglas Nixon 1 , R. Brad Jones 1 , Masahiro Yamashita 3 , Lishomwa Ndhlovu 1 , Ting Zhou 2 , Teresa H. Evering 1 1 Weill Cornell Medicine, New York, NY, USA, 2 Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3 Columbia University Irving Medical Center, New York, NY, USA Background: Neurocognitive impairment (NCI) is a prevalent and important co-morbidity in virologically suppressed people living with HIV (PWH), yet the underlying mechanisms remain elusive and effective treatments lacking. Given the limitations in models adequately replicating neuronal biology and injury in PWH, we explored the use of participant-derived directly induced neurons (iNs) for this purpose. iNs have been shown to retain age- and disease-related features of the donors, providing a unique opportunity to reveal novel aspects

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