CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Results: Baseline HRT levels in the “blip” group were significantly higher than for the “non-blip” group: median 168 vs 22 copies/10 6 cells; p<0.001. Multivariable mixed-effects logistic regression showed HRT was strongly associated with increased risk of blip within 4y [OR 3.2, CI=2.1-5.1, p<0.001] per 10-fold increase in HRT. ROC area under the curve was 0.73, (CI 0.66-079) using cut-off of 91 copies/10 6 cells, showing 71% sensitivity and 67% specificity for future blips. Baseline HIV-1 DNA copies were associated, unadjusted, with increased odds ratio of a future Blip (3.6, CI 2.4-6, p<0.001), but HIV-1 DNA did not significantly predict blips after adjustment for HRT (p=0.60). PBMC from 3 Elite controllers were negative for HRT, but in vitro stimulation of their CD4+ T cells for 1 week with anti-CD3/CD28/CD2 +IL-2 resulted in 1/10, 3/10 and 0/16 replicate cultures being positive for HRT. We also identified those with extremely low-levels of HRT had no significant brain injury in our previous dataset. Conclusions: HRT detection by the Double R assay is a scalable tool to quantify reservoir activity, independent of reservoir size, to identify potential patients with low risk of brain injury during cure research.

was less frequent in incident decline (14%, p =.005). Historical HAND was more frequent in progressing (60%, p <.04) and stable cases (61%, p =.02) versus cognitively-normal cases (11%). There were no nadir CD4 differences. Comorbidities correlated modestly with baseline neurocognition (Rho=-.23; p <.08) but not with the neurobiotypes, although progressing cases had the greatest burden. CSF RNA was associated with CSF neopterin with time variations ( Fig 1b ). Only CSF neopterin was associated MRS abnormalities (axonal injury and neuroinflammation). Conclusions: Partially compartmentalized CSF HIVRNA as measured by SCA links to neurobiotypes independently and despite comorbidities and legacy effects. Replication in larger and more diverse samples is needed. Adenosine, Guardian of the Brain: Possible Role in Protecting From HIV Neuropathogenesis Yoelvis Garcia-Mesa 1 , Fengchun Ye 1 , Sheetal Sreeram 1 , Wilber Romero Fernandez 2 , Jonathan Karn 1 1 Case Western Reserve University, Cleveland, OH, USA, 2 Vanderbilt University Medical Center, Nashville, TN, USA Background: Due to its regulatory properties, adenosine has been recognized as a guardian molecule with many protective functions in and out of the brain. For example, HIV silencing in T-cells has been associated with upregulating the adenosine-producing ecto-5’-nucleotidase Nt5e (known as CD73). We hypothesized that under HIV-induced inflammatory conditions in the brain extracellular ATP/adenosine would increase and it will lead to reduce microglial activation and silence HIV in infected microglia cells. Methods: Our studies were performed using iPSC-derived astrocytes (iA), neurons (iN), microglia iMG, and the immortalized microglia cell line HC69, a clone latently infected with a single round HIV-1 containing a short-lived GFP. Commercially available iPSC-microglia from Tempo (iMGT), which lack expression of the adenosine receptor 3 (A3), were infected with the single round reporter and used as control. HC69 monoculture and iA+HC69 coculture were used in the initial evaluation of A3 agonists and antagonists. iMG were added to the co-/tri-cultures on day 12 of differentiation, allowing them to differentiate fully. The cultures were then infected with the macrophage-tropic HIV-1 AD8 virus on day 26. The cultures were treated 24 h post-infection with 2 mM NECA (A3 agonist) or adenosine receptor antagonists (1 mM) for four days. Untreated cells were used as control. RNA and DNA were extracted and analyzed by qPCR. A decrease in the RNA-to-DNA ratio was used to measure the extent of viral suppression. Flow cytometry and microscopy were also used to evaluate HIV expression and latency. Results: Co- and tri-cultures with HIV-infected iMG showed a significant reduction of HIV expression compared to iMG/HIV monocultures. Cocultures of iA + control iMGT/HIV did not decrease HIV expression. NECA potently induced HIV latency in all cultures of HC69 and iMG/HIV but not in control iMGT/HIV. As expected, when co-cultures of iA+iMG/HIV were treated with adenosine receptor antagonists, HIV replication was not reduced. Staining of the iA+HC69 cocultures showed increased expression of CD73 in HC69 cells. Conclusions: The potent suppression of HIV expression by NECA strongly suggests that the anti-inflammatory properties of adenosine can be exploited to reduce HIV expression in the brain. This approach, which mimics the natural regulatory/homeostatic mechanisms that play a role in reducing inflammation and HIV expression in microglia cells, suggests new avenues for HIV treatment in the CNS. Neuroinflammation Associated With Levels of HIV DNA in the Frontal Cortex of Virally Suppressed PWH Sarah Byrnes 1 , Janna Jamal Eddine 1 , Jingling Zhou 1 , Emily Chalmers 1 , Michael Roche 2 , Bruce Brew 3 , Jacob D. Estes 4 , Thomas Angelovich 1 , Melissa Churchill 5 1 RMIT University, Melbourne, Australia, 2 Doherty Institute for Infection and Immunity, Melbourne, Australia, 3 St Vincent's Hospital, Sydney, Australia, 4 Oregon Health and Science University, Portland, OR, USA, 5 Royal Melbourne Institute of Technology, Melbourne, Australia Background: Currently ~30% of people with HIV (PWH) who are virally suppressed with antiretroviral therapy (ART) develop a form of HIV-associated neurocognitive disorders. The presence of a viral reservoir (and associated neuroinflammation) in the brain and ongoing systemic inflammation penetrating the brain are thought to play crucial roles. However, the precise effects of viral mediated and/or independent pathways on the brain remain ill-defined. The figure, table, or graphic for this abstract has been removed.

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Unmasking the Independent Role of CSF HIV RNA Dynamics by Single Copy Assay in Neurobiotypes Lucette A. Cysique 1 , Natasha Hills 2 , Sarah O'Donnell 2 , Kurt Lancaster 1 , Lauriane Jugé 3 , David Jakabek 1 , Thomas M. Gates 4 , Caroline Rae 3 , Sarah Palmer 5 , Bruce Brew 6 1 University of New South Wales Sydney, Sydney, Australia, 2 Macquarie University, North Ryde, Australia, 3 Neuroscience Research Australia, Randwick, Australia, 4 The University of Sydney, Sydney, Australia, 5 The Westmead Institute for Medical Research, Westmead, Australia, 6 St Vincent's Hospital, Sydney, Australia Background: In the current study, we test whether low level HIV replication is important in the pathogenesis of neurocognitive and neuroimaging biotypes, and independent of comorbidity and legacy effects. Methods: 43 virally-suppressed clinically stable men with HIV (age 53±14 years, plasma and CSF <20-50 cp/mL) were included. Neurocognition, CSF neopterin, plasma and CSF HIV RNA were measured (HIV RNA by single copy assay- SCA detection limit <0.3 cp/mL, RNA thereafter) at baseline, 6-, 12-, 18 and 24-month. Magnetic resonance spectroscopy (MRS) was conducted at baseline and 24month. Non-HIV medical, psychiatric, disability, and lifestyle history was integrated into a comorbidity score. Legacy effects were defined as historical HIV-associated neurocognitive disorder (HAND) and nadir CD4 <200. Our previous analyses had shown four neurobiotypes by neurocognitive and MRS changes. In this dataset the neurobiotypes’ prevalenc and profile were: stable=30% (mild inflammation, bioenergy abnormalities), incident decline=16.5% (increasing inflammatory activity), progressive=11.5% (axonal and neuronal injury), and cognitively-normal=42% (subclinical bioenergy abnormalities). Mixed effect models tested main effect and time-association between the neurobiotypes and the CSF biomarkers with comorbidity or legacy as covariate. Results: A pattern of intermittent RNA or lack of detectable RNA was most common (Plasma: 81%, CSF: 87%). Plasma and CSF RNA showed a transient dissociation at 6-month ( p <.005). Unlike plasma, CSF RNA was significantly increased in the progressive neurobiotype, and slightly in the stable neurobiotype ( Fig 1a ). The inclusion of comorbidities or legacy effects did not alter these results. Relative to cognitively-normal cases (50%), nadir CD4<200

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