CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

Oral Abstracts

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Low Levels of HIV-1 in CSF During ART Are Associated With Neurocognitive Impairment and Inflammation

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HIV Transcription Persists in the Brain of People With HIV and Viral Suppression Janna Jamal Eddine 1 , Thomas A. Angelovich 1 , Jingling Zhou 1 , Sarah J. Byrnes 1 , Carolin Tumpach 2 , Nadia Saraya 2 , Emily Chalmers 1 , Stephanie Marinis 1 , Paul R. Gorry 2 , Jacob D. Estes 3 , Bruce J. Brew 4 , Sharon R. Lewin 2 , Sushama Telwatte 2 , Michael Roche 2 , Melissa J. Churchill 1 1 RMIT University, Melbourne, Australia, 2 Peter Doherty Institute, Melbourne, Australia, 3 Oregon Health and Sciences University, Portland, OR, USA, 4 St Vincent's Hospital, Sydney, Australia Background: HIV persistence in the brain is a barrier to cure, and potentially contributes to HIV-associated neurocognitive disorders (HAND) that affect ~30% of people with HIV (PWH) despite viral suppression with antiretroviral therapy (ART). Persistent HIV transcription and blocks to transcription have been identified in latently infected CD4+ T cells from blood and lymphoid tissues. However, whether HIV transcription persists in the brain despite viral suppression with ART and is subject to the same blocks to transcription seen in other tissues and blood cells, is unclear. Methods: HIV transcriptional profiling of autopsy frontal cortex brain tissue from virally suppressed (n=12; undetectable plasma viral load [pVL]: <50 c/ mL; 335 CD4+ T cells/mm 3 ) and non-virally suppressed PWH (n=13; pVL: 61,223 c/mL; 8 CD4+ T cells/mm 3 ) was performed using nanowell digital PCR based assays. Associations between levels of HIV transcripts, clinical parameters, and levels of the intact and defective HIV reservoir in frontal cortex tissue as measured by IPDA were assessed by correlative analysis. Results: Frontal cortex tissue from PWH had HIV TAR (n=25/25) and Long-LTR (n=23/25) transcripts, indicative of transcriptional initiation and early elongation, respectively. Completion of HIV transcription (PolyA) and multiple splicing (Tat/Rev) was evident in frontal cortex tissue from 7/13 non-virally suppressed PWH and from 4/12 virally suppressed PWH. HIV p24 protein was also detected in all PWH with PolyA and Tat/Rev transcripts (11/11), demonstrating production of viral proteins in these individuals. Proximal and distal blocks to transcription were present in both groups. However, the block to proximal elongation (TAR → Long-LTR) was more extensive in virally suppressed PWH than in non-virally suppressed individuals (P<0.05; ratio: 2.7-fold greater block). Levels of all HIV transcripts correlated with levels of total and intact HIV proviruses (P<0.05 for all), demonstrating that the level of HIV transcription is associated with HIV reservoir size in the brain. Conclusion: These findings demonstrate that the brain is a transcriptionally active HIV reservoir in virally suppressed PWH which may contribute to ongoing neuroinflammation and HAND. Infected T-Cell Clones Are Shared Across CSF and Blood Compartments in PWH Meng Wang 1 , Jennifer Yoon 1 , Hailey Reisert 1 , Bibhuprasad Das 1 , Jennifer Chiarella 1 , John W. Mellors 2 , Alina P. Pang 1 , Joshua C. Cyktor 2 , Margaret Fikrig 1 , Elias K. Halvas 2 , Yuval Kluger 1 , Serena Spudich 1 , Michael J. Corley 3 , Shelli Farhadian 1 1 Yale University, New Haven, CT, USA, 2 University of Pittsburgh, Pittsburgh, PA, USA, 3 Weill Cornell Medicine, New York, NY, USA Background: The central nervous system (CNS) is a site of persistently infected cells during HIV infection. However, the dynamics of CNS infection and T cell trafficking in PWH are incompletely understood. Here, we utilized single-cell

Laura P Kincer 1 , Sarah B. Joseph 1 , Jessica R. Keys 1 , Natalie M. Bowman 1 , Chris Evans 1 , Alyssa Vecchio 1 , Serena Spudich 2 , Magnus Gisslén 3 , Prema Menezes 1 , Frank Maldarelli 4 , Robert Gorelick 4 , Joseph J. Eron 1 , Richard W. Price 5 , Ronald Swanstrom 1 1 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 Yale University, New Haven, CT, USA, 3 Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, 4 National Institutes of Health, Frederick, MD, USA, 5 University of California San Francisco, San Francisco, CA, USA Background: Antiretroviral therapy (ART) typically reduces HIV-1 RNA to below the limit of detection of standard vial load (VL) assays and facilitates immune reconstitution, but neurocognitive impairment (NCI) persists in many people on ART. Previous studies have suggested that higher HIV-1 cell-associated DNA and cell-free RNA levels in cerebrospinal fluid (CSF) are positively associated with neurocognitive impairment (NCI), but the mechanisms driving this association are unknown. Methods: In a cross-sectional cohort of participants (N=78) who were on ART for at least a year and lacked overt neurologic symptoms, we examined whether the amount of HIV-1 RNA in cerebrospinal fluid (CSF) during ART is associated with elevated inflammation and/or NCI. We measured neurocognition by an 11-test battery and also measured plasma and CSF VLs (by both standard [Abbott Real Time assay, limit of detection (LOD) 40 cps/ml] and single copy assays [SCA, HHMCgag assay, LOD 0.25 cps/ml]), cell counts, and 12 inflammatory biomarkers. Results: ART regimens were NNRTI- (34%), PI- (33%), and InSTI-based (29%). Median blood CD4+ T cell counts, nadir blood CD4+ T cell counts, and CSF WBC counts were 506 cells/μl, 127 cells/μl, and 1 cell/μl, respectively. The cohort was divided into three groups with increasing HIV-1 RNA levels in CSF (median, IQR cp HIV-1 RNA/ml): (1) undetectable by all assays, (2) detectable by SCA only (0.33, 0.27-1.2 by SCA), (3) detectable by standard assay (40, 40-40 by standard assay). Using Kendall's tau rank correlation (Figure 1), we observed that levels of HIV-1 RNA in CSF were positively correlated with CSF MMP9 (p=0.001), CSF protein (p=0.001), plasma TIMP1 (p=0.031) and blood CD4+ T cell count (p=0.003) and negatively correlated with total neurocognition z score (p=0.026) and speed of processing z score (p=0.011). Conclusion: We observed that during ART small increases in HIV-1 RNA that do not reach the level of treatment failure or CSF escape are associated with increased immune activation (CSF MMP9, plasma TIMP1), blood-brain barrier disruption (CSF protein) and neurocognitive impairment (total z and speed of processing z). This contributes to the growing evidence that persistent exposure to HIV-1 in the CNS during ART is associated with NCI and suggests that inflammation may play an important role in this process.

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CROI 2024