CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: Neuroinflammation in frontal cortex brain tissue from non-virally suppressed (nVS; median plasma viral load [pVL]: 4.59 log HIV RNA copies/mL; n=19) or virally suppressed PWH (VS; undetectable pVL > 2 years; n=20) was characterized at a cellular level using spatial multiplex immunofluorescence analyses. Levels of total, intact and defective HIV DNA and HIV RNA transcripts in frontal cortex tissue were quantified using digital PCR-based intact proviral DNA assay and transcriptional profiling. Results: VS PWH had undetectable plasma viral loads for a median of 5.3 years and were predominately men (86.6%). Frontal cortex tissue from VS PWH had similar levels of total and intact HIV proviral DNA compared to nVS PWH, reflecting a stable CNS reservoir of HIV that persists despite viral suppression. Frontal cortex tissue from PWH had an elevated frequency of Mx1+ or tumour necrosis factor alpha (TNFα)+ cells relative to HIV-seronegative individuals (P<0.05 for all). A higher frequency of activated myeloid cells in VS PWH was also observed. Importantly, total Mx-1 expressing cells were associated with levels of intact HIV DNA in VS PWH (P<0.001; ρ=0.658). Sub-analysis further demonstrated that both Mx-1 expressing astrocytes and CD68+ myeloid cells were both associated with levels of intact proviral DNA (P<0.01 for both), reflecting broad cellular activation in response to intact proviral genomes in frontal cortex brain tissue despite viral suppression with ART. Conclusions: Together, these findings support a role of local viral persistence and/or activation in the brain in contributing, at least in part, to neuroinflammation in virally suppressed PWH which may drive HAND pathogenesis.

Conclusions: We observed that HIV-induced inflammation in brain organoids is mediated by HIV-infected microglia and associated with changes in polyamine and tryptophan metabolism. These metabolic changes may contribute to the neuronal dysregulation observed in HAND. Plasma Neopterin as a Potential Biomarker for Neurocognitive Impairment in Aging People With HIV Anna Prats 1 , Tuixent Escribà 2 , Sonia Villanueva-Hernández 2 , Sandra González 3 , Meritxell Cucurell 3 , Ainhoa Yoldi 3 , Montserrat Alegret 4 , Mercè Boada 4 , Eugènia Negredo 1 , Bonaventura Clotet 2 , Christian Brander 2 , Roger Paredes 2 , Marta Ruiz Riol 2 , Jose A. Muñoz-Moreno 1 1 Fundació Lluita contra les Infeccions, Barcelona, Spain, 2 IrsiCaixa, Badalona, Spain, 3 Hospital Germans Trias i Pujol, Barcelona, Spain, 4 ACE Alzheimer Center, Barcelona, Spain Background: Neopterin, a biomarker of immune activation, has been widely studied in cerebrospinal fluid as a correlate of neuroinflammation and neurocognitive impairment (NCI) in people with HIV (PWH). Recent evidence suggests that plasma neopterin could be useful in identifying PWH at risk of developing NCI. This study explores neopterin as a potential plasma biomarker for NCI using 3 different cognitive screening measures in aging PWH. Methods: One hundred PWH attended at Germans Trias i Pujol Hospital, Spain, aged ≥50 years, on ART, with plasma HIV-1 RNA levels <50 copies/ml (≤6 months), were randomly selected to participate in the ALI Study ( Exploring Suggestive Symptoms of Preclinical Alzheimer's Disease in People with HIV; IRB approval: PI-21-003 ). A control group of 50 HIV-negative volunteers, matched for age, sex, and education level, was also enrolled. All participants were cognitively assessed using 3 screening tools: Mini-Mental State Examination (MMSE), FACEmemory, and NEU Screen. Plasma neopterin levels were measured by ELISA and were compared between groups and according to cognitive screening classifications. Statistical tests included the Chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. Results: Most participants were men (73%), with a mean age of 60 (±8) years, and 11 (±4) years of formal education. Positive screening for NCI was more prevalent in PWH than in controls according to the 3 screening methods, reaching statistical signification only with the NEU Screen: MMSE: 14% vs 6%, p=0.145; FACEmemory: 70% vs 56%, p=0.095; and NEU Screen: 37% vs 16%, p=0.009. Neopterin levels were higher in PWH compared to controls: 6.21 ng/ml (IQR: 3.26 - 9.14) vs 3.54 ng/ml (IQR: 2.99 - 4.82), p=0.001. Neopterin levels were also significantly higher in participants with suspected NCI compared to those without, only when using the NEU Screen classification (see Figure). Conclusions: The higher levels of plasma neopterin observed in aging PWH compared to HIV-negative individuals suggest persistent immune activation despite effective ART. Elevated neopterin levels were significantly associated with suspected NCI as measured by the NEU Screen. These results reinforce the NEU Screen as a useful NCI screening test in HIV infection, and, additionally, underscore the potential utility of neopterin as a plasma biomarker for cognitive decline in aging PWH. The figure, table, or graphic for this abstract has been removed. A Blip or a Trend? Interpreting Fluctuations in Cognition Over Time in Older Adults With HIV Marie-Josée Brouillette 1 , Marianne Harris 2 , Graham Smith 3 , Fiona Smaill 4 , Réjean Thomas 5 , Shariq Haider 4 , Scott L. Letendre 6 , Susan Scott 7 , Lesley K. Fellows 8 , Nancy E. Mayo 7 1 McGill University Health Centre Research Institute, Montreal, Canada, 2 BC Centre for Excellence in HIV/AIDS, Vancouver, Canada, 3 Maple Leaf Medical Clinic, Toronto, Canada, 4 McMaster University, Hamilton, Canada, 5 Clinique Médicale l'Actuel, Montreal, Canada, 6 University of California San Diego, La Jolla, CA, USA, 7 McGill University Health Centre, Montreal, Canada, 8 Montreal Neurological Institute, Montreal, Canada Background: Little is known about variations in cognitive performance over the long term among older adults with HIV (OAWH) and the risk of progressive cognitive decline may be overstated based on transient decline between two assessments. This analysis aimed to characterize visit-to-visit and overall evolution of cognition over up to 10 years in OAWH. Methods: 268 participants (87% men; mean duration of HIV 17.3 years, SD: 8.0; 95% undetectable) of the multisite Canadian + Brain Health Now study were followed for ≥ 5 years (mean 6 visits over 7.7 years). They were on average 53.7 years of age (range: 35.1 to 81.2). Cognition was assessed every 9-12 months using the B-CAM, a computerized battery assessing multiple domains. 1) to identify distinct groups of individuals with a similar evolution over time, we

633

Poster Abstracts

631

HIV-Infected Microglia Drive Transcriptional and Metabolic Changes in Complex Human Brain Organoids Leanne C. Helgers 1 , Pamela C. Capendale 1 , Anoop T. Ambikan 2 , Renata Vieira de Sa 1 , Theo B. H. Geijtenbeek 3 , Adithya Sridhar 1 , Ujjwal Neogi 2 , Dasja Pajkrt 1 1 Academic Medical Center, Amsterdam, Netherlands, 2 Karolinska Institute, Stockholm, Sweden, 3 Amsterdam University Medical Centers, Amsterdam, Netherlands Background: HIV enters the central nervous system early after infection which can result in HIV-associated neurocognitive disorder (HAND), affecting as many as 50% of people living with HIV (PWH). HIV-induced neuroinflammation plays a critical role in HAND. Here, we investigated the impact of HIV infection on brain inflammation and metabolism using an advanced 3D human brain organoid model embedded with HIV-infected microglia. Methods: We developed a complex human brain organoid model infused with HIV-infected microglia to capture the in vivo complexity of HIV infection in the human brain. We employed transcriptomics, coupled with genome-scale metabolic modeling to delineate metabolic and neuroinflammatory responses elicited by HIV-infected microglia in the brain. Results: Microscopy confirmed successful integration of HIV-infected microglia in human brain organoids. Expression of HIV-p24 protein was observed co-localizing with microglia and astrocytes, indicating the transfer of HIV or HIV-proteins from infected microglia to astrocytes. Moreover, HIV-induced transcriptional changes in brain organoids were abundant as illustrated by the upregulation of several inflammatory pathways, as validated by RT-qPCR. Genome-scale metabolic modeling using transcriptomic data showed impaired polyamine and tryptophan metabolism, marked by elevated spermidine levels—a metabolite previously linked to neurological impairment in clinical studies.

634

CROI 2025 173