---
title: "Monocyte phenotypes associated with peri‑coronary inflammation in people with and without HIV"
id: "frontiers-in-immunology-15-distinct-monocyte-phenotypes-are-associated-with-peri-coronary-inflammation-in"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-15-distinct-monocyte-phenotypes-are-associated-with-peri-coronary-inflammation-in"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960785"
published_at: "2026-10-20T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Monocyte phenotypes associated with peri‑coronary inflammation in people with and without HIV
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-15-distinct-monocyte-phenotypes-are-associated-with-peri-coronary-inflammation-in
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960785)
- **Published At:** 2026-10-20T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source provided the article title but did not include the article text or data needed to summarize results. Investigators and institutional details were not reported in the provided content. - The paper title indicates an association between distinct **monocyte** phenotypes and **peri‑coronary inflammation** in persons both with and without **HIV** and without clinical cardiovascular disease. - The provided content contained no description of cohort size, inclusion criteria, or participant demographics; these methodological details are therefore unavailable from the source text provided. - The source did not report laboratory methods, flow cytometry panels, imaging techniques (for peri‑coronary inflammation), or definitions of the monocyte phenotypes referenced in the title; those specifics are missing. - No quantitative results, statistical significance measures, effect sizes, or adjusted models were included in the supplied content; the study outcomes cannot be independently evaluated from what was provided. - The title implies a focus on subclinical inflammation in persons without overt cardiovascular disease; whether the study used coronary CT, PET, or other imaging modalities was not reported. - The provided material lacked adverse-event reporting, longitudinal follow‑up, or endpoint definitions; clinical implications therefore cannot be drawn from the available text. - Because primary data were not supplied, key unanswered clinical questions remain: which monocyte markers correlated with inflammation, whether associations persisted after adjustment, and how findings might affect risk stratification in people with **HIV**. - The absence of methods and results prevents assessment of bias, generalizability, or potential confounders. Readers should consult the full Frontiers in Immunology article for the complete dataset and methods before applying findings clinically.
## Clinical Analysis & Structured Key Points
Frontiers | Distinct monocyte phenotypes are associated with peri-coronary inflammation in persons with and without HIV and without cardiovascular disease ORIGINAL RESEARCH article Front. Immunol. , 20 October 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1960785 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Editor & Reviewers Edited by D M David Masson Reviewed by R K Ravi K Komaravolu Ph.D. M A Mohamed Ahmed Hussein Outline Figures and Tables Figure 1 View in article Table 1 Sociodemographic and clinical characteristics of study population. View in article Table 2 Differences in the percentages of monocyte subsets and associated cell markers between persons with and without HIV. View in article Table 3 Significant adjusted associations between monocyte subsets, associated cell surface markers, and FAI in all study participants. View in article Table 4 Significant adjusted associations between FAI and the interaction of HIV serostatus with monocyte subsets and associated surface markers (n=74). View in article ORIGINAL RESEARCH article Front. Immunol. , 20 October 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1960785 Distinct monocyte phenotypes are associated with peri-coronary inflammation in persons with and without HIV and without cardiovascular disease V R Victoria R. Stephens 1 M B Mian B. Hossain 2 J N Joshua Nordman 3 † M L Michael L. Freeman 4,5 † J J Jean Jeudy 6 † S A Shana AB Burrowes 7 M A Marcela Araujo de Oliveira Santana 8 S E Sarah E. Mitchell 9 S D Sumanth D. Prabhu 10 M M Michael M. Lederman 4 C N Celestine N. Wanjalla 1,11 ‡ N F Nicholas Funderburg 12 ‡ +4 more S B Shashwatee Bagchi 3 * 1. Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, United States 2. Department of Biostatistics, School of Community Health and Policy, Morgan State University, Baltimore, MD, United States 3. Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States 4. Rustbelt Center for AIDS Research, Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States 5. Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States 6. Section of Cardiothoracic Imaging, Department of Radiology, University of Maryland School of Medicine, Baltimore, MD, United States 7. Section of Infectious Diseases, Department of Medicine, Boston Chobanian and Avedisian School of Medicine, Boston, MA, United States 8. Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States 9. Department of Medicine, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States 10. Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States 11. Veteran’s Health Administration, Tennessee Valley Healthcare System, Nashville, TN, United States 12. Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, OH, United States See more Article metrics View details Abstract Background and objective: Chronic inflammation in persons with (PWH) and without HIV (PWoH) is linked to cardiovascular disease (CVD). The fat attenuation index (FAI), a marker of peri-coronary inflammation, predicts CVD risk. The relationship between FAI and monocyte phenotypes remains unclear. This study aimed to evaluate the relationship between monocyte subsets—classical (CD16dim intermediate/inflammatory monocytes and CD16neg), intermediate, and non-classical— and surface markers of activation and chemokine expression, and FAI in a cohort of PWH and PWoH, and compare relative differences by HIV serostatus. Methods: In this cross-sectional of a prospective observational cohort study, 58 virologically suppressed PWH and 16 PWoH without known CVD underwent coronary computed tomography angiography to measure FAI. Peripheral blood monocyte subsets and activation/homing phenotypes were analyzed via flow cytometry. Multivariable regression models assessed correlations between monocyte markers and FAI in the LAD and RCA, with interaction terms testing effects of HIV serostatus. Results: Frequency and expression of CD40 were elevated in PWH, while HLA-DR expression was lower across all monocyte subsets compared to PWoH. CD38 + intermediate monocytes were linked to worsened LAD FAI. CD38 + non-classical monocytes were correlated with worsened RCA FAI. CCR2 expression on total classical, and CD16dim, and CD16neg monocytes correlated with worsened RCA and LAD FAI, while CX3CR1 + monocytes and CD40 + subsets correlated with improved RCA FAI in adjusted analyses. Conclusions: FAI demonstrates strong correlations with monocyte phenotypes with relationships influenced by HIV serostatus, highlighting activation markers and chemokine receptor profiles as plausible drivers of vascular inflammation and FAI as a tool for detecting early immune-mediated vascular inflammation. 1 Introduction Cardiovascular disease (CVD) is the leading cause of mortality worldwide ( 1 , 2 ), and is projected to rise substantially by 2050 ( 3 ). Hence, there is significant clinical interest in identifying blood and radiologic markers that may predict the onset of early disease and/or serve as targets for developing early interventional and preventive strategies. Until the development of the fat attenuation index (FAI), noninvasive quantification of subclinical coronary artery inflammation was not feasible. FAI measures compositional changes in perivascular fat to assess coronary inflammation using standard coronary computed tomography angiography (CCTA) ( 4 ), enabling the quantification of early-stage inflammation in the three major coronary arteries: the right coronary artery (RCA), the left anterior descending artery (LAD), and the left circumflex coronary artery ( 5 ). FAI has also been shown to predict major cardiac mortality and major adverse cardiovascular events (MACE), regardless of the presence of CVD risk factors or structural coronary artery disease ( 5 , 6 ). Persons with HIV (PWH) have a two-fold higher risk of developing CVD than persons without HIV (PWoH) ( 7 ). The elevated risk in PWH may be attributed in part to chronic inflammation and persistent immune activation ( 8 – 10 ). Monocyte infiltration and polarization play pivotal roles in regulating atherogenesis through the inflammation of perivascular adipose tissue and the formation, destabilization, and rupture of plaques, facilitated by the release of a variety of cytokines and chemokines ( 11 – 14 ). Monocytes are traditionally differentiated based on expression of the lipopolysaccharide receptor CD14 and the FcyIII receptor CD16. Single-cell transcriptomic studies and reviews indicate that human monocytes form related but distinct populations shaped by subset-specific transcriptional networks and epigenetic programming ( 15 – 19 ). Regulon-based network inference distinguishes classical (CD14++CD16-) from nonclassical (CD14+CD16++) monocytes through different transcription factor–centered activity profiles (e.g., HMGB2/CREB5/FOSB-enriched programs in classical cells versus TCF7L2/POU2F2-associated programs in nonclassical cells), while intermediate (CD14++CD16+) monocytes show overlapping regulon activity consistent with a transitional state along a continuous trajectory inferred by pseudotime ( 15 ). In addition, trained-immunity paradigms demonstrate that prior stimulation can induce durable chromatin and metabolic alterations that reconfigure subsequent transcriptional responses and yield multiple trained monocyte states detectable at single-cell resolution, with related signatures observed in inflammatory disease settings (e.g., ulcerative colitis, sepsis, COVID-19) ( 16 ). Together, these data demonstrate that monocyte subsets are not solely CD14/CD16-defined phenotypes but transcriptionally and epigenetically programmed populations with specialized roles in inflammatory effector functions, migration, and tissue/vascular surveillance ( 17 , 19 ) and that substantial heterogeneity can also exist within subsets across individuals and health/disease states ( 18 ). In humans, three distinct monocyte subsets are conventionally defined based on expression of CD14, CD16, and chemokine receptors: classical (CD14++CD16-) monocytes; which express CCR2; intermediate (CD14++CD16+) monocytes, which express both CCR2 and CX3CR1 (and relatively more CCR5 than do classical monocytes); and nonclassical (CD14+CD16++) monocytes, which do not express CCR2 but typically express a high frequency of CX3CR1 among monocyte subsets ( 11 , 20 ). Functionally, these subsets are increasingly recognized as nonredundant effectors across inflammatory and antiviral contexts: classical monocytes are broadly pro-inflammatory, with robust capacity to secrete soluble mediators and to differentiate into monocyte-derived dendritic cells, thereby contributing to the crosstalk between innate and adaptive immunity; intermediate monocytes are enriched for antigen presentation and have been linked to immune activation during HIV infection; and nonclassical monocytes are commonly associated with antiviral surveillance and response programs ( 19 ). Advancements in flow cytometry have enabled the re-examination of the heterogeneity of various cellular subsets ( 21 , 22 ), including the conventional blood-derived monocytes ( 23 ). Monocyte subsets have distinct functions, including cytokine production and antigen presentation ( 24 – 26 ). CD16-expressing monocyte subsets are often implicated as being more pro-inflammatory ( 27 , 28 ), but less is known about their in vivo activities, and discrepancies exist regarding the association between CD16-expressing monocytes and atherosclerosis ( 29 , 30 ). Prior studies have shown the roles of monocyte subsets in atherosclerotic CVD (ASCVD) among PWoH ( 27 , 30 – 33 ). Numbers of non-classical and intermediate monocytes have been shown to be elevated in PWH compared to those of PWoH, with higher levels in PWH correlating with increased viremia, T cell activation, and plasma IL-6 levels ( 34 ). Interestingly, the monocyte activation profile in uncontrolled HIV infection was similar to that of acute coronary syndrome (ACS) in PWoH ( 20 ). However, there is a paucity of studies evaluating monocyte subsets between PWoH and PWH, and none have evaluated the relationship between monocytes defined by this extended gating and subclinical measures of atherosclerosis using CCTA and measuring peri-coronary inflammation (FAI). Our group has previously reported associations between peri-coronary inflammation, as assessed by FAI values, and markers of systemic inflammation and T lymphocyte activation in persons asymptomatic for ASVCD and found that certain inflammatory pathways were prominent and more robustly associated with FAI in PWH than among PWoH ( 35 , 36 ). In this study, we evaluated the relationship between monocyte subsets—classical (including CD16dim intermediate/inflammatory monocytes and CD16neg), intermediate, and non-classical— and surface markers of activation and chemokine expression, and FAI in a cohort of PWH and PWoH, and compared differences by HIV serostatus. Finally, we explored correlations of specific monocyte phenotypes with the soluble inflammatory markers and circulating T cell phenotypes we have previously evaluated in these donors, to generate testable hypotheses for future mechanistic studies. 2 Methods 2.1 Study participants and procedures Fifty-eight adult PWH virologically suppressed on ART for at least six months and 21 adult PWoH from a parent prospective observational study (four study groups, also including hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected) that was conducted and IRB-approved (IRB# HP-00074189) at the University of Maryland (UMD) to assess coronary plaque changes with direct-acting antiviral treatment were included in the current study. We have previously described the inclusion and exclusion criteria of the parent observational study ( 35 – 38 ). Briefly, all participants in the current analysis were seronegative for hepatitis C virus (HCV), and PWoH were age- and sex-matched to PWH with otherwise identical inclusion/exclusion criteria and were recruited and enrolled from the same clinics. Participants with and without HIV were enrolled using identical eligibility criteria, with participants without HIV age- and sex-matched to those with HIV. We recruited both groups through the same sources, including participating clinics, ResearchMatch.org, and a university campus newsletter for faculty, staff, and students. HIV infection was defined by prior documentation of a confirmed reactive anti–HIV antibody test or a positive HIV antigen/antibody combination assay. We defined hepatitis C virus (HCV) infection as a confirmed reactive anti-HCV antibody test; all participants included in the present analysis were anti-HCV antibody–negative. History of atherosclerotic cardiovascular disease (ASCVD) was initially obtained by participant self-report and then verified by comprehensive review of electronic medical records from the University of Maryland Medical Center and outside institutions (including records from prior hospitalizations and emergency department visits), after participants provided written authorization for release of medical information; study eligibility was determined only after this verification was completed. Major exclusion criteria included: presence of unstable coronary syndromes or symptoms suggestive of ACS; systolic blood pressure >160 mmHg; low-density lipoprotein cholesterol (LDL-c) >160 mg/dL; poorly controlled diabetes mellitus (defined as a need for anti-glycemic therapies and/or HbA1c >7%); hemoglobin 40 were removed from the original sample to make the BMI between study groups more comparable, since BMI was found to have the strongest association with FAI in our cohort ( 37 ). 2.2 CCTA and measurement of FAI CCTA was performed using a third-generation dual-source CT scanner (SOMATOM Force; Siemens Medical Solutions, Forchheim, Germany) from September 2017 to June 2021 and analyzed as we have described in a prior publication ( 37 ). Peri-coronary fat attenuation was measured around the proximal RCA and LAD and was defined as the mean attenuation of all adipose-containing voxels between −190 and −30 Hounsfield units obtained from the outer wall of the vessel within a radius equal to the vessel diameter. A total length of 40 mm from the proximal portion of the RCA and LAD was measured, and the proximal 10 mm of the RCA were excluded to limit artifacts from the aortic wall. FAI analysis was performed by two radiologists who were blinded to participant serostatus, and the senior radiologist performed quality control, supervision, and assurance of the analyses. 2.3 Flow cytometry analysis Cryopreserved human peripheral blood mononuclear cells (PBMCs) from PWH and PWoH were thawed, washed twice in Hank’s Balanced Salt Solution (HBSS) containing 2% fetal bovine serum (FBS) and counted. Staining was performed by mixing pellets of 2x10 ( 6 ) cells with 50 µL antibody mixture at 4°C for 45 min, followed by washing twice in 0.5% FBS-HBSS. Antibodies were diluted in 0.5% FBS-HBSS, and the optimal dilution of each antibody had been determined beforehand. All antibodies were purchased from BioLegend (San Diego, CA). Stained cells were immediately analyzed by polychromatic flow cytometry using a FACSAria II flow cytometer (BD Biosciences). We subdivided the classical monocytes into two subsets based on the expression of CD16 (CD16neg vs. CD16dim intermediate/inflammatory monocytes). To test whether the CD16dim intermediate/inflammatory monocytes and CD16neg subpopulations presented distinct subpopulations within the classical monocyte population, an unsupervised principal component analysis (PCA) was performed based on the 11-color flow cytometry (FlowJo, FlowJo LLC. Ashland, OR) ( 39 ). To rule out variations among PWoH, PBMCs from five additional healthy donors were used for the monocyte subpopulation classification analyses. The boundary between these two provisional subpopulations was rigorously determined by a fluorescence-minus-one control for the CD16 staining. To assess the expression levels of each surface marker, we independently analyzed percent positivity (with negativity defined by staining with an isotype control antibody) and mean fluorescence intensity (MFI). This approach was necessary because some markers exhibited high positivity rates (>90%), which could compress the range of variation within subsets and potentially obscure statistically significant differences. Detailed information on the monocyte antibody panel and the flow cytometry gating strategy can be found in the Supplementary Data . Flow data were analyzed using FlowJo software, version 10 (FlowJo LLC). 2.4 Statistical analysis We summarized and compared sociodemographic factors, behavioral indicators, clinical indicators, and mean FAI of both RCA and LAD between PWH and seronegative controls (PWoH). We restricted our analyses to the RCA and LAD because the original CRISP CT study found that the RCA and LAD FAI values predicted mortality and cardiac events ( 4 ), reflecting the spatially heterogeneous nature of atherosclerosis. Assumption of normality was checked for each continuous variable using Q-Q plots and Shapiro-Wilk test. For normally distributed continuous variables, an independent samples t-test was used to examine the difference between groups. For continuous variables that did not meet normality assumptions, a non-parametric Mann-Whitney U test was used to examine the difference between groups. For categorical variables, the Chi-square test or Fisher’s Exact test were used as appropriate to examine differences. We analyzed the correlations (via Pearson’s or Spearman’s rank, as appropriate) and partial correlations of the percentages of monocyte subsets and their associated cell surface markers (both percentages and MFI) with mean FAI (RCA and LAD separately) in all study participants, controlling for age, sex, race, LDL-c, lipid-lowering medication use, and BMI. All covariates, except BMI, are presented as dichotomous variables, while BMI was presented as a continuous variable. For each model, we assessed the interaction between HIV serostatus and monocyte subset percentages and marker expression and adjusted for the confounders. Additional analyses were conducted to assess correlations between soluble markers of inflammation and the monocyte subsets, as well as their associated surface markers. Simple Pearson’s correlations were examined in unadjusted and partial correlations were examined in adjusted analyses. Soluble markers assessed were IL-6, sTNF-R1, sTNF-R
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