CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Results: Overall, PWH had a lower CD4:CD8 ratio both in the peripheral blood [0.8 (0.5 – 1.28) vs 2.05 (1.6 – 3.7) p<0.001] and in the colon [0.9 (0.6-1.4 vs 1.7 (1.2-2.9)), p<0.0001] compared to HIV-NC. Among PWH, 26 (50%) individuals had colonic CD4:CD8 >1. This subset of PWH were more likely female (62% vs 38%, p=0.0158), diagnosed with HIV for a longer time [31 (18-32) vs 19(10-24) years, p=0.0347] have longer duration of most recent viral suppression [7(4-12) vs 4(2-8)years, p=0.0365] higher CD4+ T cells at enrollment [607 (453 – 947) vs 462 (294 – 664) p= 0.0262] and higher CD4+ T cell nadir [200 (92 – 306) vs 162 (39- 193)]. Multiple logistic regression showed that duration of HIV infection [OR 1.13 (95% C.I. 1.02-1.3)] and CD4= T cell nadir[OR 1.01 (95% C.I. 1.001 1.016)] were associated with colonic CD4:CD8 >1. Colonic CD4:CD8 ratio partially correlated with the peripheral blood CD4:CD8 ratio (r=0.274, p=0.068) and with the pro-inflammatory cytokines IL-20 (r= -0.413, p=0.036) and SLAMF-1 (r= -0.329, p=0.074). Conclusions: In PWH, CD4:CD8 ratio<1 is associated with persistent elevation of inflammatory parameters. Nadir CD4+ T cells and longer duration of HIV infection are the best predictors of normalization of intestinal CD4:CD8 ratio. Living With HIV Mimics the Pro-Inflammatory FUT2 Non-Secretor Phenotype in the Intestines Leila B. Giron 1 , Maliha W. Shaikh 2 , Shivanjali Shankaran 2 , Phillip A. Engen 2 , Michelle Villanueva 2 , Ceylan E. Tanes 3 , Kyle Bittinger 3 , Alan Landay 4 , Michael J. Corley 5 , Ali Keshavarzian 2 , Mohamed Abdel-Mohsen 1 1 Northwestern University, Chicago, IL, USA, 2 Rush University, Chicago, IL, USA, 3 Children's Hospital of Philadelphia, Philadelphia, PA, USA, 4 University of Texas Medical Branch, Galveston, TX, USA, 5 Weill Cornell Medicine, New York, NY, USA Background: The genetic FUT2 non-secretor status is phenotypically characterized by low levels of the glycan α1,2 fucose. Fucose in the intestines plays a crucial role in maintaining homeostasis between the gut and its microbiota, and loss of fucose can impair intestinal function and promote inflammation. While intestinal dysfunction and inflammation are well documented in people with HIV (PWH), the potential link between the non-secretor genotype or phenotype and these pathological features remains unclear. Methods: Ileum and colon biopsies, along with fecal samples, were collected from 25 PWH on antiretroviral therapy and 23 matched controls without HIV. Secretor genotype (based on rs516246 SNP) and FUT2 expression were determined by qPCR. Fucose levels in the ileum and colon were measured using a lectin array. Intestinal permeability was assessed by evaluating tight junction protein (ZO-1 and Occludin) expression through immunohistochemistry. Plasma markers of microbial translocation and inflammation were measured using multiplex arrays. Biological aging in the ileum, colon, and blood was assessed via epigenetic aging clocks. Fecal microbiota composition was analyzed using 16S rRNA sequencing. Results: There was no difference in the frequency of the non-secretor genetic status between PWH and controls (p=0.3) or in FUT2 expression in the ileum or colon (p>0.5). However, phenotypically, α1,2 fucose levels were significantly reduced in the ileum (p<0.001; Fig. A) and colon (p=0.002) of PWH than controls. Lower fucose correlated (p<0.05) with increased intestinal permeability, elevated markers of microbial translocation (including Zonulin, LBP, sCD14), higher inflammatory markers (including CXCL9), and accelerated biological aging, as measured by the DunedinPACE and Horvath epigenetic clocks (Fig. B). Finally, lower fucose levels were linked to a dysbiotic microbiota, characterized by increased pro-inflammatory bacteria and reduced beneficial short-chain fatty acid producing bacteria (p<0.05). Conclusions: Despite being genetically classified as secretors, PWH exhibit a non-secretor phenotype in their intestines, characterized by reduced levels of the anti-inflammatory fucose. This phenotype is associated with disrupted microbiota, compromised intestinal integrity, heightened inflammation, and accelerated biological aging. Understanding the mechanisms underlying this phenotype and its consequences may pave the way for developing novel strategies to prevent inflammation-associated comorbidities in PWH.

cluster 3 by gut epithelial dysfunction, T-cell activation, systemic inflammation; cluster 3 phenotype being associated with a 7-fold increased risk of prevalent cardiovascular disease (CVD). We aimed to determine the transcriptional pathways associated with these distinct inflammatory phenotypes in PWH compared to a demographically similar HIV uninfected control group. Methods: Within a cohort of treated PWH and HIV uninfected controls, the samples with the shortest Euclidean distance to the centroid of each of the above clusters were used to identify three PWH groups who were the most representative of each inflammatory cluster and an HIV uninfected control group matched in age (±5years), smoking status, sex, BMI, and ethnicity. We measured gene expression in peripheral blood mononuclear cells using the NanoString immune exhaustion 800 genes panel. Differential expression (DE) was defined as ±1.5 foldchange and P<0.05 was considered significant. HIV uninfected group was used as a baseline for DE gene analyses. Reactome Voronoi tool was utilised to show the overrepresented pathway topologies of DE genes. Results: 143 (87.4% PWH) participants were included in the analysis, median age of 45 years, 56% male, and 30% current smokers. After adjusting for multiple comparisons using the Benjamini-Hochberg to estimate the false discovery rate, 206 genes were DE in PWH compared to the HIV uninfected controls (Table 1), with 103 genes shared across the three inflammatory clusters. The overrepresented pathway topologies of adaptive immune system, cytokine signalling, and innate immune system were shown in cluster 1 (low-inflamed), programmed cell death topology was overrepresented in cluster 2, while the CVD associated cluster 3 unique gene list mapped to regulation of lipid metabolism, pyroptosis, and cellular immune senescence. Conclusions: Distinct inflammatory profiles in PWH that are linked to altered risk of CVD, map to specific transcriptional pathways involved in lipid metabolism, pyroptosis and immune senescence. These insights suggest distinct pathways that may offer therapeutic targets to further reduce impact of CVD in PWH.

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Poster Abstracts

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Intestinal CD4:CD8 Ratio and Systemic Inflammatory Parameters in Suppressed HIV-1 Infection Francesca Cossarini, Pablo Canales-Herrerias, Divya Jha, Michael Tankelevich, Alexandra E. Livanos, Saurabh Mehandru Icahn School of Medicine at Mount Sinai, New York, NY, USA Background: With successful antiretroviral therapy (ART), while peripheral CD4+ T cells may reconstitute in most people with HIV (PWH), CD8+ T cells often remain elevated. The resulting inversion of CD4:CD8 ratio (<1) is associated with adverse clinical outcomes including non-AIDS malignancies and cardiovascular disease. The gut-associated lymphoid tissue (GALT) endures significant CD4+ T cell depletion starting during acute HIV infection. Here we determined the heterogeneity in CD4:CD8 ratio in a well-characterized cohort of PWH and investigated the predictors of intestinal CD4:CD8 ratio reconstitution (CD4:CD8>1) and its impact on systemic inflammation. Methods: We enrolled 52 PWH on ART and with peripheral HIV-RNA<20 copies/ ml, as well as 37 HIV-negative controls (HIV-NC) who underwent colonoscopy. T-cell subsets were analyzed via multiparameter flow cytometry. Peripheral inflammatory cytokines with a multiplexed proteomic inflammation panel (Olink®). Descriptive statistics are expressed as n(%) or Median(interquartile range (IQR)) as appropriate. Comparisons were performed with Mann-Whitney U test or Spearman correlation as appropriate. Multiple logistic regression was used to estimate odds ratio (OR).

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CROI 2025