CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

848

CHIP Is Associated With Plasma Inflammatory Biomarkers and Vascular Events in People With HIV on ART Caroline H. Sheikhzadeh 1 , Alton Barbehenn 1 , Stephanie Kuang 1 , Sonia Savur 1 , Danny Li 1 , Xiuping Chu 2 , Colin T. Maguire 3 , Rafick P. Sekaly 4 , Jeffrey A. Tomalka 4 , Brian Agan 5 , Anuradha Ganesan 6 , Joseph Yabes 7 , Alexander Bick 6 , Priscilla Hsue 8 , Sulggi Lee 1 1 University of California San Francisco, San Francisco, CA, USA, 2 Infectious Disease Clinical Research Program, Bethesda, MD, USA, 3 University of Utah, Salt Lake City, UT, USA, 4 Emory University, Atlanta, GA, USA, 5 Uniformed Services University of the Health Sciences, Bethesda, MD, USA, 6 Walter Reed National Military Medical Center, Bethesda, MD, USA, 7 Brooke Army Medical Center, San Antonio, TX, USA, 8 University of California Los Angeles, Los Angeles, CA, USA Background: CHIP (clonal hematopoiesis of indeterminate potential) mutations (hereafter ‘CHIP’) are acquired somatic DNA mutations that are associated with increased risk of cancer, mortality, and vascular disease. People with treated and suppressed HIV (PWH) have higher frequencies of CHIP than people without HIV (PWoH), but the underlying mechanisms linking CHIP and clinical events remains unclear among PWH or PWoH. Methods: We sampled 1000 PWH on ART from the U.S Military HIV Natural History Study using a case-cohort design: 200 PWH with incident vascular events (VE) and 800 PWH without VE. CHIP (e.g., DNMT3A , TET2 , ASXL1 ) were quantified by PCR from PBMCs and cytokines were measured from plasma (MesoScale). We analyzed two composite clinical outcomes: atherogenic VE (AVE: coronary artery disease, myocardial infarction, cerebrovascular accident, or peripheral arterial disease) and VE (deep vein thrombosis, pulmonary embolus, or AVE). Cox proportional hazard models were performed to estimate the risk of AVE/VE, including covariates for traditional vascular risk factors and HIV disease progression (Fig 1). Linear mixed effects models were fit to estimate 2-fold changes in cytokines associated with CHIP. Results: The median baseline age was 39, and 92% of participants were male. 56 of 975 sequenced participants (5.7%) had detectable CHIP (3 participants had >1 CHIP mutation). The most common CHIP variant was in DNMT3A . CHIP was associated with incident AVE (HR AVE =2.24, 95%CI=1.19-4.24) and VE (HR VE =2.21, 95%CI=1.24-3.91), even after adjustment for hyperlipidemia and hypertension (aHR AVE =1.81, 95%CI=0.99-3.31; aHR VE =1.82, 95%CI=1.07-3.10). However, this effect was largely driven by the middle age tertile and did not meet statistical significance after age adjustment (Figure 1A). This may be due to lower incidence of CHIP and VE in the lowest age tertile and competing risks in the highest tertile. CHIP was associated with several cytokines (IL-6, IP-10, MCP-3, MIP-3a) of which IP-10 remained statistically significant after adjustment for age (Fig 1B). Conclusions: CHIP mutations were associated with incident VE/AVE in PWH on ART. These data are the first to highlight circulating immune pathways potentially involved in CHIP-mediated pathogenesis, especially in PWH (e.g., IP-10 is a critical proinflammatory factor responding to IFN-γ in HIV disease). Further studies are needed to compare the risk of CHIP in PWH vs. PWoH and determine whether the identified cytokine pathways are unique to PWH. The figure, table, or graphic for this abstract has been removed. ALDH Activity as a New Marker of Subclinical Atherosclerosis During ART-Treated HIV-1 Infection Jonathan Dias 1 , Etiene Moreira Gabriel 2 , Tomas Raul Wiche Salinas 3 , Abdelali Filali-Mouhim 4 , Sylla Mohamed 4 , Marc Messier-Peet 2 , Julie Moreaux 4 , Madeleine Durand 4 , Carl Chartrand-Lefebvre 2 , Jean-Pierre Routy 5 , Nicolas Chomont 2 , Mohamed El-Far 4 , Cécile Tremblay 2 , Petronela Ancuta 2 1 University of Montreal, Montreal, Canada, 2 Université de Montréal, Montreal, Canada, 3 Emory University, Atlanta, GA, USA, 4 Centre de Recherche du CHUM, Montreal, Canada, 5 McGill University Health Centre Research Institute, Montreal, Canada Background: Antiretroviral therapy (ART) controls viral replication in people with HIV (PWH), but viral reservoirs (VR) persist and represent a cause for the occurrence of age-related comorbidities, e.g. cardiovascular disease (CVD). We demonstrated that retinoic acid (RA, a vitamin A derivative) increases HIV-1 outgrowth from VR and that microbiota components (e.g., Staphylococcus aureus) promote ALDH (aldehyde dehydrogenase that converts vitamin A into RA) activity in myeloid cells. We hypothesized that ALDH activity is a novel functional marker of immune activation that predicts subclinical atherosclerosis in ART-treated PWH. Methods: This study was conducted on PBMCs of ART-treated PWH (HIV+ART; n=42) and uninfected subjects (HIV-; n=40) from the Canadian HIV and Aging Cohort Study (CHACS), with/without subclinical coronary artery atherosclerosis

CMV may have more atherosclerosis in part due to increased CMV activity in macrophages that infiltrate vascular tissues.

847

Endothelial Colony-Forming Cells From People With HIV Display an Interferon Gene Signature Akif A. Khawaja 1 , Robert Maughan 1 , Ishrat Jahan 1 , Lida Kabir 2 , Koralia Paschalaki 1 , Mark Nelson 3 , Ruth Byrne 3 , Anna Randi 1 , Graham Taylor 1 , Charis Pericleous 1 , Marta Boffito 3 , Michael Emerson 1 1 Imperial College London, London, UK, 2 MRC Laboratory of Medical Sciences, London, UK, 3 Chelsea and Westminster NHS Foundation Trust, London, UK Background: People with HIV (PWH) have an increased risk of cardiovascular disease (CVD), however, the underlying mechanisms are not fully understood. Endothelial dysfunction is central to CVD pathology. Endothelial colony-forming cells (ECFC) arise from endothelial progenitors isolated from whole blood and retain the donor’s phenotypic characteristics ex vivo. ECFC are increasingly used to study disease-specific mechanisms in patient cohorts but have been largely overlooked in HIV research. We therefore isolated ECFC from PWH and people without HIV (PWoH) either with or without Pre-Exposure Prophylaxis (PrEP) exposure, to explore differences in ECFC biology. Methods: Whole blood was obtained from PWH on fully suppressive antiretroviral therapy, PWoH accessing PrEP or not on PrEP attending HIV care or prevention clinics at Chelsea and Westminster Hospital. ECFC were isolated from peripheral blood mononuclear cells (PBMC). DNA and RNA was extracted from ECFC at passage 4. Proviral HIV DNA was measured by qPCR using primers and probes for the integrase gene. mRNA expression of interferon (IFN) signalling (e.g. IFI44 , ISG15 , MX1 ), thromboinflammation (e.g. F3 , EDN1 , VCAM1 ) and mitochondrial-metabolic (e.g. MTDN1 , IDH1 ) markers was quantified by RT-PCR using SYBR Green. Results: ECFC were isolated from PWH (PLWH-ECFC; n=8, 75% male, 87.5% white), PWoH accessing PrEP (PrEP-ECFC; n=9, 100% male, 88.9% white) and PWoH not on PrEP (NP-ECFC; n=3, 100% male, 66.7% white). A higher frequency of ECFC colonies were recovered from PLWH compared to people on PrEP when normalised to number of PBMC seeded (0.53 vs 0.13 vs colonies/1x10 6 PBMC, p=0.0085). In PLWH, proviral HIV DNA was detected in matched PBMC but not in ECFC (1.7 vs 0.0 copies/10 4 cells, p=0.0002). Elevated IFN, thromboinflammatory, mitochondrial and metabolic associated gene expression was seen in PLWH-ECFC relative to NP- and PrEP-ECFC. IFN gene expression strongly correlated with inflammatory and metabolic genes. Conclusions: PWH displayed higher ECFC frequencies, although the clinical significance of this is unclear. Despite the absence of proviral HIV DNA, PLWH ECFC displayed an IFN gene signature which positively correlated with elevated inflammatory and metabolic markers. Collectively, our observations indicate endothelial dysfunction in PLWH-ECFC despite fully suppressive ART, that may be driven by IFN signalling. Further investigation is required to fully define mechanisms of endothelial dysfunction and to identify therapeutic targets in PWH.

Poster Abstracts

849

CROI 2025 258