CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

579

Tryptophan and Kynurenine Pathway Activation and Cognition in Virally-Suppressed Women With HIV Eran F Shorer 1 , Raha M. Dastgheyb 2 , Audrey L. French 3 , Elizabeth Daubert 4 , Ralph Morack 4 , Clary B. Clish 5 , Kevin Bullock 5 , Deborah Gustafson 6 , Anjali Sharma 7 , Andrea Rogando 4 , Qibin Qi 8 , Helen Burgess 9 , Leah H. Rubin 1 , Kathleen Weber 4 1 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 The Johns Hopkins University, Baltimore, MD, USA, 3 Stroger Hospital of Cook County, Chicago, IL, USA, 4 Hektoen Institute of Medicine, Chicago, IL, USA, 5 Broad Institute of MIT and Harvard, Cambridge, MA, USA, 6 State University of New York Downstate Medical Center Downstate Medical Center, Brooklyn, NY, USA, 7 Montefiore Medical Center, Bronx, NY, USA, 8 Albert Einstein College of Medicine, Bronx, NY, USA, 9 University of Michigan, Ann Arbor, MI, USA Background: Dysregulated immune function and cognitive complications persist in people with HIV (PWH) despite viral suppression. Inflammatory cytokines and HIV proteins induce the enzyme IDO (indoleamine 2, 3-dioxygenase) to convert tryptophan (T) to kynurenine (K) while producing reactive oxygen species and downstream neurotoxic metabolites, which may lead to cognitive complications. Using the KT ratio as a surrogate marker, we investigated the relationship between IDO activation and cognition in virally suppressed women with HIV (VS-WWH) and women without HIV (WWoH). Methods: 99 VS-WWH on stable antiretroviral therapy (median age = 54, 73% Black) and 102 (median age = 52, 75% Black) demographically similar WWoH from Chicago and New York sites of the Women's Interagency HIV Study (WIHS) completed a neuropsychological test battery assessing motor function, processing speed, attention/working memory, verbal fluency, verbal learning and memory, and executive function. Plasma tryptophan and kynurenine were measured using liquid chromatography-tandem mass spectrometry, and targeted plasma monocyte-derived (sCD163, sCD14, MCP-1/CCL2) and general inflammatory markers (TNFR-II, hsCRP, hsIL-6) were measured using enzyme linked immunosorbent assay (ELISA). Results: VS-WWH had a higher KT ratio (P<0.01) and higher sCD14 levels (P<0.05) compared to WWoH. In false discovery rate-corrected multivariable regression analyses, higher KT ratio was related to worse motor function in VS-WWH (r = -0.33, P<0.05). This relationship was independent of inflammatory markers. No relationship between IDO activation and motor function was observed in the WWoH. Conclusion: IDO activation was associated with worse fine motor control in VS-WWH independent of measures of systemic inflammation. Further studies are required to investigate the biological mechanisms linking IDO activation to cognitive complications including poor fine motor function among PWH, despite having well-treated HIV. Impact of Recombination on HIV-1 Evolutionary Dynamics in CSF and Plasma Li Li 1 , Leslie St. Bernard 2 , Daniel Dunn 2 , Douglas F. Nixon 2 , Weigang Qiu 1 , Teresa H Evering 2 1 Hunter College, New York, NY, USA, 2 Weill Cornell Medicine, New York, NY, USA Background: HIV-1 is capable of establishing distinct viral populations within CNS, leading to a spectrum of neuronal complications. An improved understanding of HIV-1 evolutionary dynamics across the CNS and plasma is necessary to inform vaccine and cure efforts and longitudinal assessments are lacking. Methods: We used single genome amplification to generate full-length HIV-1 env (>2.5Kb) clade B variants from the paired CSF and plasma of 13 chronically infected individuals living with HIV from the CHARTER cohort with no neurocognitive impairment (N=6) and asymptomatic or mild neurocognitive disease (N=7). Participants were viremic and either treatment naïve (N=6) or experienced (N=7). Each participant contributed viral samples from two time points separated by 6 to 48 months. We used phylogenetic analysis to determine viral compartmentalization and genetic divergence. Recombination was detected using both RDP and ClonalFrameML packages. dN/dS analysis was conducted in DnaSP6 software to assess selection force. BEAST software was used to estimate env DNA substitution rate. Results: We analyzed 1300 confirmed single genome sequences. Compartmentalization between CSF and plasma was observed in 11 out of 13 participants in at least one of two time points. In analyses of combined time points, plasma-derived variants showed higher sequence diversity (0.0302 vs 0.0247 in average nucleotide difference, p=0.016), divergence from the origin (0.0830 vs 0.0639 substitutions/site, p=0.041), recombinant frequency (0.147

Results: Twenty-five percent of the study participants had CSF NfL levels above normal reference limits prior to initiation of ART. Following 12 months of ART, a significant reduction in mean NfL levels was observed (-27 %, p < 0.005); however, no significant decline was noted after three months of treatment (-12 %, p > 0.05). No further change in NfL levels was observed after 24 or 36 months of ART. CSF levels of YKL-40, sTREM2 and neopterin significantly declined after both 3 and 12 months while GFAp did not decline significantly at neither 3 nor 12 months. Notably, strong correlations were observed between all evaluated biomarkers at baseline and all except neopterin at 12 months. Conclusion: The decrease of NfL as well as biomarkers of immune activation suggests that ART significantly reduces axonal injury as well as neuroinflammation within one year of treatment initiation. The significant decrease of inflammatory biomarkers, but not NfL, after three months indicate that reduction of neuroinflammation precedes reduction of neuronal harm. Protein Modifications by Lactate Associate With Lower Risks of Neurocognitive Impairment and Death Danying Cao 1 , Liangliang Zhang 1 , James Galligan 2 , Corrilynn O. Hileman 3 , Asha Kallianpur 4 , Alan Landay 5 , Ronald J. Ellis 6 , Frank Palella 7 , Susan L. Koletar 8 , Katherine Tassiopoulos 9 , Robert C Kalayjian 3 1 Case Western Reserve University, Cleveland, OH, USA, 2 University of Arizona, Tucson, AZ, USA, 3 MetroHealth Medical Center, Cleveland, OH, USA, 4 Cleveland Clinic, Cleveland, OH, USA, 5 Rush University, Chicago, IL, USA, 6 University of California San Diego, La Jolla, CA, USA, 7 Northwestern University, Chicago, IL, USA, 8 The Ohio State University, Columbus, OH, USA, 9 Harvard TH Chan School of Public Health, Boston, MA, USA Background: In response to diverse infections, macrophages shift their main metabolism from oxidative phosphorylation to aerobic glycolysis, with lactate as the end-product. Ensuing increases in glycolytic flux promote the production of advanced glycation end products (AGEs), reactive glucose metabolites that alter protein function via non enzymatic, post-translational modifications (PTMs). These PTMs can modify cellular metabolism and they associate with adverse clinical outcomes. Lysine (Lys) lactoylation is a PTM that is derived from the transfer of a lactate moiety from the glyoxalase cycle intermediate, lactoylglutathione (LGSH), to a free Lys residue (hence 'lactoyl Lys'). These modifications are elevated during periods of increased glycolytic flux. In human cell cultures, this PTM was recently shown to inhibit glycolysis by disproportionally affecting glycolytic enzymes. We hypothesized that metabolic reprogramming from HIV-1 infection induces similar PTMs that contribute to enhanced AGEs-associated morbidities. Herein, we examined associations by plasma concentrations of selected AGEs and glutathione species with incident neurocognitive impairment (NCI) and all-cause mortality. Methods: Plasma concentrations of 12 AGEs and 3 glutathione species were assayed by liquid chromatography–mass spectrometry, in stored specimens collected at entry from 376 randomly selected participants of a prospective AIDS Clinical Trials Group cohort of PWH (HAILO). Cox PH models explored associations with clinical outcomes, adjusted for possible confounders. Cognition was assessed by Trailmaking A&B, Digit Symbol and Hopkins Verbal Learning tests at entry and every 48 wks. Results: Among 376 participants, with a mean f/u of 244 wks, there were 10 deaths and 104 incident NCI cases. Higher LGSH concentrations associated with a lower hazard of NCI [aHR 0.80; 0.65-0.99] while higher lactoyl Lys protein concentrations associated with lower hazard of both NCI [aHR 0.74; 0.58-0.96] and death [aHR 0.29; 0.09-0.93]. Conclusion: The observed protective associations by LGSH and lactoly Lys proteins may represent a counter-regulatory response to the adverse effects of enhanced glycolysis, supporting a possible role by metabolic reprograming to the enhanced NCI and mortality risks of PWH. Future studies within this nested cohort will examine associations by AGEs with additional comorbidities.

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Poster Abstracts

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CROI 2024 159