CROI 2025 Abstract eBook

Abstract eBook

Oral Abstracts

167

Brain Volume Normalization After 96 Weeks of ART Started During Acute HIV Infection Robert Paul 1 , Jacob Bolzenius 1 , Phillip Chan 2 , Carlo Sacdalan 3 , Donn Colby 4 , Julie Mannarino 1 , Lydie Trautmann 5 , Serena Spudich 2 , Victor Valcour 6 , Somchai Sriplienchan 3 , for the RV254/SEARCH 010 Study Team 1 University of Missouri St Louis, St Louis, MO, USA, 2 Yale University, New Haven, CT, USA, 3 SEARCH, Bangkok, Thailand, 4 US Military HIV Research Program, Bethesda, MD, USA, 5 Henry M Jackson Foundation, Bethesda, MD, USA, 6 University of California San Francisco, San Francisco, CA, USA Background: Previous studies on brain volumes in people with HIV (PWH) who initiated antiretroviral therapy (ART) during acute HIV infection (AHI) were limited by the absence of a control group or brief follow-up periods. A recent cross-sectional analysis revealed larger volumes in regions vulnerable to HIV during AHI. Here, we compared longitudinal brain volume changes over 96 weeks between RV254 AHI cohort participants and people without HIV (PWoH). Methods: The study included 119 RV254 AHI cohort participants and 45 demographically matched PWoH from Thailand, all of whom underwent two 3T brain MRI approximately 96 weeks apart. RV254 participants underwent the 1st MRI and completed the Patient Health Questionnaire (PHQ-9) for depressive symptoms, and a 4-test cognitive battery during AHI and prior to ART initiation at week 0. AHI participants achieved HIV suppression by week 24, and underwent the 2nd MRI at approximately 96 weeks post-ART. Brain volumes were quantified using voxel-based morphometry and summed across hemispheres. Repeated measures compared volumes within and between the groups. Correlations examined associations between brain volumes with cognitive performance (NPZ-4) and the PHQ-9 score at week 0 for the PWH group, with adjustments for multiple comparisons. Results: Both groups were similar in age, education, and comorbidities. All RV254 participants were male, with a median age of 28, median CD4+ T-cell count of 412 (IQR 277-664) cells/mm 3 , and median plasma HIV RNA of 6.66 (IQR 5.73-6.90) log 10 cps/ml at week 0. Both groups exhibited smaller brain volumes in most regions at week 96 compared to week 0 with no evidence of accelerated volume loss among PWH. At week 0, larger volumes were observed among

168

Spinal Cord as a Distinct Site of HIV Persistence and Dispersal in the Brain Mattia Trunfio 1 , Cheryl Dullano 1 , Stephanie Solso 1 , Gemma Caballero 1 , Pinyi Du 1 , Brady Lapke 1 , Caroline Ignacio 1 , Magali Porrachia 1 , Patricia K. Riggs 2 , Davey Smith 1 , Antoine Chaillon 1 , Sara Gianella Weibel 1 1 University of California San Diego, La Jolla, CA, USA, 2 University of California San Diego Medical Center, La Jolla, CA, USA Background: The HIV reservoir in the central nervous system (CNS) poses a significant challenge to cure efforts, mostly by our limited understanding and access to this compartment. Methods: Tissue samples across 9 CNS regions, including 5 spinal cord (SC) segments (pons, medulla, cervical, lumbosacral, and thoracic spinal cord [TSC], frontal motor cortex [FC], basal ganglia [BG], hippocampus [HP], and occipital cortex [OC]), and peripheral blood mononuclear cells (PBMCs) were collected during rapid autopsies (≤6 hour from death) from people with HIV enrolled in the Last Gift cohort. For each tissue, we measured cell-associated HIV DNA and RNA by ddPCR. Adjusted mixed-effects models compared the HIV reservoir measures across tissues. Single genome HIV-1 env sequencing (SGS, Illumina) and T cell receptor repertoire (TCR) sequencing were performed in a subset of participants. Bayesian phylodynamic and generalized linear models evaluated viral dispersal and associated factors. Tree- and distance-based methods evaluated compartmentalization. Results: Twenty participants were evaluated: mean age 63±13 years, 85% males, median current CD4+ T cells 193/µL, 85% with plasma HIV RNA <40 cp/ mL. While HIV DNA levels in all the SC segments were lower compared to those in PBMCs (p<0.0001), they did not differ from the other CNS regions, except for higher HIV DNA in TSC compared to OC (p=0.039). HIV RNA levels were also similar across the CNS, except for BG that had higher HIV transcriptional activity compared to all the other CNS tissues and PBMCs (p<0.05 all). HIV-1 env diversity (entropy) in TSC was higher compared to that in FC and HP (p<0.05 both). In the 8 participants with SGS and TCR sequencing (≥4 CNS regions including TSC), phylodynamic models revealed viral migration between the SC segments and across the other CNS regions in all participants (e.g., Fig.A ). Viral diversity, divergence, and TCR overlap (Morisita index) between CNS locations were not associated with HIV migration. Clear evidence of compartmentalization of HIV in the SC compared to the virus in the rest of the CNS and in PBMCs was supported in 2 and 3 participants, respectively (e.g., Fig.B ). Conclusions: This study provides a comprehensive characterization of the HIV reservoir and its dynamics within the human SC. The SC contributes to HIV persistence and replenishment of brain reservoirs and can be a distinct site of compartmentalization within the CNS. Larger studies are needed to fully understand the SC's role in reseeding peripheral tissues. Longitudinal Persistence of HIV DNA in CSF Over 4 Years Despite Up to 20 Years of ART Joshua C. Cyktor 1 , Evgenia Aga 2 , Asma Naqvi 1 , Dianna Hoeth 1 , Ronald J. Bosch 2 , Bernard J. Macatangay 1 , Joseph J. Eron 3 , Susan Koletar 4 , Deborah McMahon 1 , John W. Mellors 1 , Serena Spudich 5 , Rajesh T. Gandhi 6 , Constance A. Benson 7 , for the ACTG A5321 Study Team 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 4 The Ohio State University, Columbus, OH, USA, 5 Yale University, New Haven, CT, USA, 6 Harvard Medical School, Boston, MA, USA, 7 University of California San Diego Medical Center, La Jolla, CA, USA Background: The central nervous system (CNS) reservoir for HIV during ART has implications for both HIV cure and clinical outcomes. HIV DNA has been cross-sectionally detected in cerebrospinal fluid (CSF) cells but the longitudinal dynamics of HIV DNA in CSF during long-term suppressive ART are unknown. Methods: 16 participants in ACTG A5321/A5341s who started ART during chronic infection and had documented long-term suppression of plasma HIV RNA underwent 4-5 serial lumbar punctures (LP) over a span of 2.4-4.4 years. Cell pellets from ~13mL of CSF were assayed for total HIV DNA and cell-associated HIV RNA; cell-free HIV RNA by single copy assay was measured from CSF supernatant. Geometric means of longitudinal measurements were calculated using censored data methods, analyzing both quantifiable and below assay limit values, and used for Spearman correlation analyses. Results: The participants (100% male) had a median (IQR) age of 56 (50, 59) years, and were on ART for median 9 (range 6-16) years at their first LP. All participants had HIV DNA detected in CSF at one or more time points, and in total, 48/79 samples assayed had detectable HIV DNA. 11/16 participants (69%) had

Oral Abstracts

169

PWH compared to PWoH in the hippocampus and thalamus with no differences between groups at week 96, consistent with normalization after ART. Amygdala and nucleus accumbens volumes were lower among PWH at week 0 without progressive volume loss. Among the AHI participants, larger hippocampal and caudate volumes at week 0 correlated with worse depressive symptoms and lower NPZ-4 score (p<.05). Conclusions: We observed no evidence of more rapid brain atrophy in these young, healthy AHI individuals who initiated ART during acute infection compared to healthy PWoH. Larger brain volumes in select regions at week 0 (pre-ART) correlated with worse neurobehavioral indices, with normalization in brain volumes following sustained viral control.

The figure, table, or graphic for this abstract has been removed.

42

CROI 2025