Understanding Residual Risk of Cardiovascular Disease in People Living with HIV

Abstract

Purpose of Review

Traditional cardiovascular risk factors, combined with persistent systemic inflammation, contribute to the increased prevalence of atherosclerotic cardiovascular disease (ASCVD) in people living with HIV (PLWH). This review highlights key findings from the REPRIEVE trial on statin-based primary prevention of major adverse cardiovascular events in PLWH. It explores HIV-specific immune mechanisms contributing to residual cardiovascular risk.

Recent Findings

In REPRIEVE, statin therapy used for primary prevention of major adverse cardiovascular events in PLWH decreased the plasma lipoprotein-associated phospholipase A2, oxidized low-density lipoprotein, and high-sensitivity C-reactive protein (hs-CRP). However, several inflammatory markers including soluble CD14 (sCD14), sCD163, interleukin (IL)-1β, IL-6, IL-10, and caspase 1 did not change. The HIV reservoir, dysfunctional CD4⁺ T cells, immunoglobulin G N-glycans, anti-apolipoprotein A1 autoantibodies, trained immunity, and clonal hematopoiesis of indeterminate potential may contribute to residual inflammation.

Summary

Despite antiretroviral and statin therapy, residual ASCVD risk in PLWH underscores the need for targeted interventions. Anti-inflammatory therapies, including IL-6 and IL-1β inhibitors, CCR5 antagonists (e.g., maraviroc, cenicriviroc mesylate), and immunomodulatory agents like methotrexate and colchicine, are being explored. Understanding HIV-driven immune dysregulation may lead to novel strategies to mitigate cardiovascular risk in this population.

INTRODUCTION

Despite advances in antiretroviral therapy (ART), people living with HIV (PLWH) face a heightened risk of cardiometabolic diseases, particularly atherosclerotic cardiovascular disease (ASCVD)(1–4). Persistent immune activation and chronic inflammation, hallmarked by elevated levels of interleukin (IL)-1β (5, 6), soluble (s)CD14, sCD163, and CRP (7–9) , remain central drivers of vascular damage and plaque formation (10). These inflammatory pathways persist even with effective viral suppression, contributing to residual cardiovascular risk despite optimal management of traditional risk factors, including statin therapy (Figure 1) (11).

Figure 1. Residual risk of cardiovascular disease in PLWH.

Multiple factors contribute to CVD risk in PLWH. The top panel highlights key risk factors, including HIV infection, lifestyle behaviors (smoking, unhealthy diet, inactivity, and drug use), obesity, diabetes, genetic predisposition, heavy alcohol consumption, high blood pressure, and elevated cholesterol and triglycerides, which collectively increase the risk of CVD. The middle panel categorizes these risks into modifiable habits (e.g., smoking, physical inactivity, unhealthy diet, and heavy alcohol use) and treatable conditions (e.g., high cholesterol, high blood pressure, diabetes, and HIV infection). The bottom panel addresses residual CVD risks in PLWH, such as chronic inflammation, dyslipidemia (cholesterol and triglycerides), increased thrombotic risk, and elevated lipoprotein (a), along with their association with gut microbiome dysregulation, ongoing HIV-related effects, and co-infections.

The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) showed that statins effectively reduce cardiovascular events in PLWH, with additional benefits in lowering lipid oxidation and arterial inflammation (12, 13). However, no significant changes were detected in other inflammatory markers, including sCD14, sCD163, IL-1β, IL-6, IL-10, and caspase 1 (13). These findings prompted a change in clinical guidelines in 2024, recommending statins for primary ASCVD prevention in PLWH aged 40 years and older with a 10-year risk estimate between 5% and <20%.

Chronic inflammation in PLWH is not solely driven by viral replication. This is because ART-naïve elite controllers also have increased inflammatory markers compared to PWoH, suggesting that immune activation is an intrinsic feature of HIV infection (14, 15). This inflammatory environment promotes vascular dysfunction and underscores the need for novel therapeutic strategies targeting immune pathways beyond lipid regulation. Anti-inflammatory therapies, such as the IL-1β inhibitor canakinumab, reduced cardiovascular events in the general population but had infection-related safety concerns (16). Trials in PLWH have yielded mixed results, highlighting the complexity of managing inflammation in this population (17–19).

Despite advancements in statin therapy and ongoing research into immune-targeted interventions, residual cardiovascular risk remains a critical challenge for PLWH. A comprehensive understanding of the interplay between HIV persistence, chronic immune activation, and cardiovascular pathophysiology will inform the development of tailored therapies and improve long-term outcomes for this population (Table 1).

Table 1.

Recent relevant publications

Interest level	Title	Journal/Year/Volume/Issue/Pages	Authorship	PMID	Reason for interest	REF
Immunoglobulin G N-glycan & Apolipoprotein A1 antibodies [B cell Responses]
*	Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection	Nat Commun. 2024 Apr 10;15(1):3035	Leila B. Giron, Qin Liu, Opeyemi S. Adeniji, Xiangfan Yin, Toshitha Kannan, Jianyi Ding, David Y. Lu, Susan Langan, Jinbing Zhang, Joao L. L. C. Azevedo et al.	38600088	This study shows changes in N-glucans among PLWH compared to PWoH. Specifically, there are increased pro-inflammatory glycans and lower anti-inflammatory glycans. These are associated with circulating inflammatory markers and diseases of aging such as atherosclerotic cardiovascular disease. Furthermore, using machine learning model, the N-glycans may be used to estimate biological age #MACS/WIHS Cohort	(41)
*	People living with HIV display increased anti-apolipoprotein A1 autoantibodies, inflammation, and kynurenine metabolites: a case-control study	Front. Cardiovasc. Med., 2024;11:1343361	Miguel A. Frias, Sabrina Pagano, Nasim Bararpour, et al.	38414919	Highlights elevated anti-apoA1 IgG levels and their association with pro-inflammatory biomarkers and kynurenine pathway activation in PLWH. This auto-immune response links immune activation to vascular inflammation and CVD risk.	(113)
T cell Responses
**	Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28− CD8 T Cells in HIV Infection and Atherosclerosis via the CD2–LFA-3 Axis	Journal of Immunology, 2024, Vol 212, Issue 2, Pages 245–257	Nicole E. Winchester, Soumya Panigrahi, Anokhi Haria, et al.	38047900	The study shows how CMV coinfection may promote pro-inflammatory CD8 T cells through CD2–LFA-3 interactions, promoting chronic vascular inflammation and atherosclerosis.	(55)
*	Development and validation of a predictive model for metabolic syndrome in a large cohort of people living with HIV	Virol J. 2024 Dec 19;21:321	Suling Chen, Yuyuan Xu, Yuanhui Jiang, Hongjie Chen, Xiaoxuan Wu, Zhe Qian, Xuwen Xu, Huiqun Zhong, Jie Peng, Shaohang Cai	39702185	This study presents a potential model that may be used by researchers to assess and predict the risk of metabolic syndrome among PLWH. Several factors in their model including CD8+ T cells, γ-GT and lactate dehydrogenase were important in the predictive models. #Population: Nanfang, China 2022–2023	(112)
**	Distinct immune profiles in children living with HIV based on timing and duration of suppressive antiretroviral treatment	Virology. 2025;602:110318. Epub 20241126	Lee MJ, Litchford ML, Vendrame E, Vergara R, Ranganath T, Fish CS, Chebet D, Langat A, Mburu C, Neary J, Benki S, Wamalwa D, John-Stewart G, Lehman DA, Blish CA	39612623	This study compares immune profiles in children living with HIV based on the timing and duration of ART. Key findings include: Early long-term ART: Associated with higher proportions of CD4+ T cells, naïve CD4+ and CD8+ T cells, and increased expression of markers such as CCR2, CCR5, CD7, and CD127, which support cell survival, homeostasis, and trafficking. Mature cytotoxic NK cells (CD56dim CD16hi) were also higher in this group, suggesting more effective immune functionality. Delayed short-term ART: Linked to higher proportions of CD8+ T cells, effector memory (TEM), and terminally differentiated effector memory RA+ (TEMRA) cells. Higher levels of exhaustion markers (PD-1, CD155) and stress proteins (LLT-1, MICA/B, Nectin-2, and ULBP family proteins) were observed, particularly on TEM cells. Monocyte clusters, including those expressing CD3 and CD14, were also increased.	(44)
	Death and survival of gut CD4 T cells following HIV-1 infection ex vivo	PNAS Nexus, Volume 3, Issue 11, November 2024, pgae486	Kaylee L Mickens, Stephanie M Dillon, Kejun Guo et al	39780917	This study explores mechanisms of gut CD4 T cell depletion in HIV-1 infection. It highlights the role of microbial translocation and granzyme B in promoting apoptosis, linking gut immune dysregulation to systemic inflammation and elevated CVD risk. Survival pathways, such as CD120b/TNFR2 signaling, suggest novel therapeutic targets.	(48)
Clonal Hematopoiesis of Indeterminate Potential [CHIP]
*	Risk Factors for Clonal Hematopoiesis of Indeterminate Potential in People with HIV: A Report from the REPRIEVE Trial	Blood Advances, 2024, Vol 8, Issue 4, Pages 959–970	Romit Bhattacharya, Md Mesbah Uddin, et al.	38197863	Links clonal hematopoiesis (CHIP) in PLWH to increased risk of cardiovascular conditions, emphasizing the interaction between genomic factors, CD4 nadir, and atherosclerosis. CHIP drives vascular inflammation and dysfunction, contributing to residual CVD risk.	(114)
Systemic Inflammatory Markers
**	Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy-Treated Individuals With Undetectable Viremia	Journal of Infectious Diseases, 2024;229(3):763–774	Mehdi Benlarbi, Jonathan Richard, et al.	38035854	Elevated sgp120 levels are associated with immune activation and inflammatory cytokines like IL-6, contributing to vascular inflammation and atherosclerotic plaque formation.	(115)
**	Systemic Inflammation With High-Sensitivity C-Reactive Protein and Atherosclerotic Plaque Progression	JACC Cardiovascular Imaging, 2024;17(2):212–213	Solomon Bienstock, Sang-Eun Lee, Fay Lin, et al.	37921719	The study highlights how hsCRP levels correlate with the progression of non-calcified atherosclerotic plaques. Elevated hsCRP predicts a 2-fold higher risk of plaque progression, emphasizing inflammation’s role in residual CVD risk.	(116)
*	Association of Cardiac Troponin T With Coronary Atherosclerosis in Asymptomatic Primary Prevention People With HIV	JACC Advances, 2024;3(9):101206	Christopher deFilippi, Sara McCallum, Markella Zanni, et al.	39253712	Identifies high sensitivity -cardiac Troponin T as a marker for subclinical coronary atherosclerosis, correlating with vulnerable plaque characteristics. The study emphasizes its utility in stratifying CVD risk among asymptomatic PLWH​.	(117)
Lipoprotein (a)
*	Lipoprotein(a) Is Elevated and Inversely Related to Coronary Endothelial Function in People With HIV	J Am Heart Assoc., 2024;13:e035975	Daniel S. Kikuchi, Yaa A. Kwapong, Michael Schär, et al.	39575706	Demonstrates that Lp(a) levels are significantly higher in PLWH and inversely correlate with coronary endothelial function (CEF). The study emphasizes Lp(a) as a contributor to residual CVD risk via impaired endothelial vasoreactivity.	(118)
*	Association of Lipoprotein(a) with peri-coronary inflammation in persons with and without HIV infection	Journal of Clinical Lipidology, 2024;18:e430-e443	Erin Zisman, Mian Hossain, Nicholas T. Funderburg, et al.	38403541	Demonstrates that Lp(a) levels correlate with peri-coronary inflammation and systemic immune activation. The Fat Attenuation Index (FAI) reveals inflammation near coronary vessels in PLWH, linking Lp(a) to subclinical atherosclerosis.	(119)
Inflammasome
*	Chronic HIV Infection Increases Monocyte NLRP3 Inflammasome-Dependent IL-1α and IL-1β Release	International Journal of Molecular Sciences, 2024, Vol 25, Article 7141	Hedda Hoel, Tuva Børresdatter Dahl, et al.	39000248	Highlights how inflammasomes like NLRP3 contribute to persistent inflammation in PLWH, exacerbating comorbid conditions like CVD. Inflammasome activation drives vascular inflammation and plaque progression, with IL-1β being a key mediator.	(120)
**	HIV Infection Drives Foam Cell Formation via NLRP3 Inflammasome Activation	Int. J. Mol. Sci., 2024;25(2367):1–12	Maurizio Caocci, Meng Niu, Howard S. Fox, Tricia H. Burdo	38397063	Demonstrates that HIV infection promotes foam cell formation and upregulates NLRP3 inflammasome activation, leading to increased IL-1β and IL-18 secretion. These findings link innate immune activation with vascular inflammation in PLWH.	(109)
Gut Microbiome
**	Sex Hormones, the Stool Microbiome, and Subclinical Atherosclerosis in Women With and Without HIV	Journal of Clinical Endocrinology & Metabolism, 2024;109(2):483–497	Brandilyn A. Peters, David B. Hanna, Yi Wang, et al.	37643897	This study identifies sex hormones as predictors of gut microbiome diversity and their interplay in women living with HIV. Findings suggest that estrogens, through their influence on the gut microbiome, mediate protective cardiovascular effects by reducing carotid artery plaque. This is among the first explorations linking the “estrobolome” and microbial pathways to subclinical atherosclerosis in PLWH.	(121)
*	Distinct Gut Microbiota Signatures Associated With Progression of Atherosclerosis in People Living With Human Immunodeficiency Virus	Journal of Infectious Diseases, 2024, Vol 229, Pages 13–21	Mar Masiá, José A. García, Javier García-Abellán, et al.	38743815	Identifies specific gut microbiota signatures linked to atherosclerosis progression in PLWH, such as increased Agathobacter and Ruminococcus and decreased Prevotella. Microbial dysbiosis drives systemic inflammation and vascular damage, highlighting therapeutic targets for CVD.	(111)
Other
*	Stroke, HIV and the Immune Reconstitution Inflammatory Syndrome in the absence of opportunistic infections	Journal of Neurological Sciences, 2024, Vol 457, Article 122880	Eitzaz Sadiq, Sarah Katzew, Jeremy Nel, et al.	38219384	Investigates the 3.5-fold higher stroke risk in PLWH within six months of ART initiation. Study found that stroke incidences correlated with immune reconstitution inflammatory syndrome, emphasizing a link to non-opportunistic inflammatory mechanisms.	(122)
*	Mineralocorticoid Receptor Antagonism by Eplerenone and Arterial Inflammation in HIV: The MIRABELLA HIV Study	JAMA Cardiology, 2024, Vol 9, Issue 2, Pages 189–194	Suman Srinivasa, Shady Abohashem, et al.	38090987	Demonstrates the impact of eplerenone in reducing arterial inflammation in PLWH, with reductions correlating to improved myocardial perfusion. Highlights the potential of anti-inflammatory therapies to mitigate residual CVD risk.	(123)

THE HIV RESERVOIR

ART effectively prevents the spread of HIV to new cells but cannot eliminate infected cells, resulting in chronic immune activation and inflammation in PLWH (20). Several studies on the HIV reservoir suggest that inflammatory states significantly influence the reservoirs’ distribution and size, with greater activation levels leading to larger reservoir sizes (21, 22). The persistence of memory CD4⁺ T cells through homeostatic and antigen-driven proliferation maintains the HIV reservoir despite prolonged ART (23–25). This reservoir can be quantified by measuring HIV DNA levels in memory CD4⁺ T cells (26), while its activity is inferred from HIV RNA levels in circulating cells (27, 28). Although much of the HIV DNA may be defective and incapable of producing infectious virions, it can still generate viral proteins that stimulate immune responses (29, 30). Persistent reservoirs sustain low-level antigenic stimulation, fueling chronic immune activation and systemic inflammation (20). HIV persistence arises from multiple mechanisms, including long-lived latently infected CD4⁺ T cells (31), cryptic viral replication (32, 33), and impaired HIV-specific T-cell responses (34). Chronic inflammation disrupts HIV-specific T cells, reducing their capacity to eliminate infected cells (35, 36). Immune exhaustion, driven by the upregulation of negative regulators like the programmed cell death protein 1 (PD-1), further enriches the HIV reservoir (21). PD-1 high CD4⁺ T cells harbor high levels of integrated HIV DNA and impair HIV-specific immunity (21).

IMMUNE TARGETS AND RESIDUAL CVD RISK IN PLWH

N-GLYCAN LEVELS AND CIRCULATING INFLAMMATORY MARKERS

Glycosylation is a critical post-translational modification of circulating immunoglobulin G (IgG) antibodies, involving the addition of glycans primarily to the Fc region and, to a lesser extent, to the Fab region (37). Fc glycosylation significantly influences the antibody’s non-neutralizing functions, which can be either anti-inflammatory or pro-inflammatory (38). Changes in IgG glycosylation accumulate with biological and chronological aging and are exacerbated in individuals with age-related diseases, including CVD (39). These glycosylation changes can be detected years before the clinical onset of age-related conditions (40). Research by Giron LB et al. has shown that PLWH exhibit sex-dependent variations in IgG N-glycan profiles. Specifically, PLWH have lower levels of anti-inflammatory glycans, such as sialylated and terminally galactosylated structures, and higher levels of pro-inflammatory glycans, including agalactosylated and bisected N-acetylglucosamine (GlcNAc) (41). Elevated pro-inflammatory N-glycan levels positively correlate with inflammatory markers like IP-10, CXCL9, sCD14, sCD163, MIP-1α, and TNF-α. Conversely, higher levels of anti-inflammatory N-glycans negatively correlate with these markers (41). The presence of agalactosylated and bisected GlcNAc structures is linked to increased inflammation and severe coronary atherosclerosis in PLWH (41). These findings suggest that glycan profiles could be predictive biomarkers for aging-related comorbidities, including the residual risk of ASCVD among PLWH.

T CELLS AND INFLAMMATORY CYTOKINES

Chronic immune activation in PLWH contributes to heightened inflammation and endothelial dysfunction, key drivers of CVD risk (1). CD4⁺ T cell depletion, incomplete immune reconstitution, and sustained CD8⁺ T cell activation further promote vascular dysfunction (42, 43). Differences in immune markers on T cells in children with HIV include increased CCR2 and CCR5 in the early ART group and PD-1, CD155, and stress proteins (Lectin-Like Transcript 1 (LLT1), MHC Class I Polypeptide-Related Sequence A and B (MICA/B), and Nectin Cell Adhesion Molecule 2 (Nectin-2)) with delayed ART (44). These immune alterations may have long-term implications; expression of CCR2 and CCR5 is linked to monocyte recruitment and vascular inflammation, while PD-1, CD155, and stress-associated ligands could contribute to immune exhaustion and endothelial dysfunction—key drivers of ASCVD in PLWH.

Among PLWH, early HIV infection is characterized by CD4⁺ T cell depletion in the gastrointestinal tract, undermining mucosal immunity and disrupting epithelial barriers (45, 46). This CD4⁺ T cell depletion is exacerbated by gut microbes, which enhance CD4⁺ T cell infection with HIV, hence cell death by apoptosis (47). A study by Mickens KL showed that gut granzyme B (GZB⁺) CD4⁺ T cells exposed to E coli had increased HIV-1 infection compared to gut GZB^- CD4⁺ T cells (48). While GZB⁺ CD4⁺ T cells infected with HIV primarily undergo cell death by apoptosis, there is a subset of cells of GZB⁺ CD4⁺ T cells that express survival factors related to TNF receptors such as CD120b/TNFR2 that may also support HIV-1 persistence and contributing to HIV reservoirs in the gut. The persistence of GZB⁺ CD4⁺ T cells with survival markers such as CD120b/TNFR2 introduces new considerations for the intersection of HIV persistence and chronic inflammation. These cells not only harbor high levels of HIV-1 but also promote ongoing immune activation, a recognized driver of residual CVD risk in PLWH.

Activated T cells release inflammatory cytokines such as interferon-gamma (IFN-γ) (49), TNF-α, and IL-6, exacerbating systemic inflammation, endothelial activation, and vascular damage (50). IFN-γ drives macrophage activation and foam cell formation, while IL-6 and TNF-α amplify inflammatory pathways, promoting a pro-thrombotic state. Cytotoxic CD8⁺ T cells expressing granzyme B and perforin may directly damage endothelial cells, worsening vascular dysfunction (51). Additionally, dysfunctional regulatory T cells and impaired immune checkpoints exacerbate inflammation and destabilize immune regulation.

CMV infection is associated with death from cardiovascular disease in PLWH (52). CMV-specific CD4 T-cells (CGC: CX3CR1⁺ GPR56⁺CD57⁺) have been associated with subclinical atherosclerosis among PLWH (53) , and higher carotid intima thickness has been independently correlated with CMV-specific T cells (54). Pro-inflammatory CMV-specific CD8⁺ T cells express CD2 and promote chronic vascular inflammation and atherosclerosis through interactions with LFA-3 on endothelial cells (55).

TRAINED IMMUNITY IN PLWH

Trained immunity is the long-term metabolic and epigenetic reprogramming of innate immune cells, such as dendritic cells, NK cells, monocytes, macrophages (56), and non-immune cells, such as endothelial cells and vascular muscle cells (57, 58), resulting in enhanced inflammatory responses upon re-exposure-to-unrelated stimuli (56). While this mechanism evolved to protect against recurrent infections, it can become maladaptive under chronic immune activation, contributing to inflammatory diseases (59, 60). In PLWH, persistent immune activation driven by microbial translocation, residual viral replication, and coinfections provides ongoing stimuli for trained immunity (61). Monocytes from PLWH display transcriptional and functional profiles indicative of trained immunity, including upregulation of inflammatory pathways mediated by IL-6 and TNF-α (5, 62), reduced ABCA1 expression, and impaired cholesterol efflux (63, 64). This heightened inflammatory state may drive immune cell recruitment to vascular tissues, macrophage foam cell formation, and plaque instability, all key contributors to ASCVD.

In PLWH, elevated plasma β-glucan levels, likely due to microbial translocation across compromised gut barriers, correlate with increased cytokine responses and systemic inflammatory markers such as sCD14 and hs-CRP (65). HIV proteins, particularly Nef, amplify this inflammatory process by activating the Akt-mTOR pathway, promoting glycolysis and epigenetic reprogramming that sustain inflammation (66). Exosomal Nef may also influence bone marrow progenitors, promoting trained monocyte production (63, 67, 68). This self-sustaining inflammatory loop contributes to atherogenesis and other CVD-related pathologies. Trained immunity likely develops in two phases during HIV infection: an initial phase during active viral replication characterized by robust inflammatory responses and epigenetic reprogramming and a second phase after ART, marked by prolonged low-level exposure to extracellular Nef and low-grade inflammation (63, 69, 70). The second phase may involve epigenetic changes affecting lipid raft dynamics (59, 63).

Metabolic rewiring associated with trained immunity, including increased glycolysis and cholesterol biosynthesis in PLWH (71), may also exacerbate foam cell formation and atherosclerosis progression (59, 72). Furthermore, histone modifications may affect pro-inflammatory cytokine production, perpetuating vascular inflammation (69, 73). Strategies that target trained immunity may be an additional approach to reduce residual CVD risk in PLWH. Statins have been shown to inhibit trained immunity induction by β-glucan and oxLDL in vitro (74), though they cannot reverse established epigenetic changes in hypercholesterolemic patients (75). Alternative approaches include interventions targeting metabolic pathways, such as the Akt-mTOR axis, or reversing epigenetic reprogramming using histone-modifying enzyme inhibitors.

CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP)

CHIP is the age-associated acquisition of somatic mutations in hematopoietic stem cells (HSCs), which confer a selective growth advantage, leading to the clonal expansion of mutant hematopoietic cells (76). CHIP is defined by the presence of such mutations with a VAF (variant allele frequency) ≥2% in the absence of overt hematological malignancy or other diagnostic criteria for clonal hematopoietic disorders (77, 78) and commonly occurs in older ages (76). Frequently mutated genes include DNMT3A, TET2, ASXL1, JAK2, and TP53, which regulate critical processes such as DNA methylation, chromatin remodeling, cytokine signaling, and genomic stability (79, 80). The pathophysiology of clonal dominance in CHIP is largely unknown; however, multiple studies have suggested a relationship between CHIP and inflammation (81–83). Although the causal relationship between HIV infection and chronic immune inflammation is well-documented, the extent to which a persistent HIV-induced inflammatory state promotes CHIP is unclear.

Studies have demonstrated that having CHIP mutations increases the risk of CVD and all-cause mortality (82, 84–86). Mechanistically, CHIP mutations, particularly in TET2 and DNMT3A, cause preferential monocytic differentiation of HSCs and alter gene expression in mature monocytes/macrophages via the NLRP3/IL-1β/IL-6 pathway (85, 86). For example, murine studies have shown that loss of TET2 in HSCs led to increased production of IL-1β, macrophage activation, and accelerated atherosclerotic plaque development (81, 82). The IL-1β inhibitor, canakinumab, also reduced CVD events in individuals with TET2 mutations (17, 87). Similarly, JAK2 mutations, which hyperactivate the JAK-STAT pathway, are associated with endothelial dysfunction, thrombosis, and vascular inflammation (88–90), further implicating CHIP as a driver of CVD.

In PLWH on ART, the combination of CHIP and chronic immune activation may amplify the risk of CVD. PLWH have a higher incidence of CHIP mutations (91–94), particularly in TET2, DNMT3A, and ASXL1 genes, (82, 92) than age-matched PWoH. Persistent inflammation, a hallmark of treated HIV, is hypothesized to accelerate the clonal expansion of mutated hematopoietic cells, increasing the prevalence and impact of CHIP (91, 95). CHIP and HIV infection have been associated with a significant increase in IL-6 and CRP (92). Moreover, PLWH with clonal hematopoiesis (VAF > 1%) were more likely to have coronary stenosis of at least 50% than those without clonal hematopoiesis (94). This is consistent with findings by Bick et al., who reported an increased prevalence of the ASXL1 gene and risk of CVD in PLWH (91). In a separate study, PLWH had more CHIP and larger clone sizes (VAF>20%) than population controls. CHIP was associated with low CD4 nadir, increased residual HIV-1 transcriptional activity, and increased coagulation factors (D-dimer and von Willebrand Factor) in PLWH (96). In addition to inflammatory markers, increased circulating levels of coagulation factors have been associated with increased mortality and CVD risk in PLWH (97). The connection with the HIV reservoir is particularly interesting, given that many key CHIP driver genes are involved in epigenetic modification, such as DNA methylation (98). HIV transcription depends on epigenetic modifications, cell differentiation, activation, and low-grade inflammation (96).

Sub-acute or chronic inflammation drives clonal hematopoiesis, likely due to the increased resistance of mutated clones to inflammatory signals (99–101). Thus, induced inflammation in PLWH, potentially in combination with patient-related factors such as age and comorbidities, could increase the risk of clonal hematopoiesis development, further promoting inflammation and negatively affecting innate immunity. CHIP has been suggested as a biomarker for predicting future CVD events in PLWH without traditional risk factors (102). Screening for CHIP mutations in high-risk populations, including older adults and PLWH, may help identify individuals with elevated CVD risk who could benefit from targeted anti-inflammatory interventions.

INFLAMMASOME ACTIVATION IN HIV

The NLRP3 inflammasome plays a central role in vascular inflammation by sensing cellular stress and activating caspase-1, which promotes the release of IL-1β and IL-18 and pyroptotic cell death (103). This inflammatory pathway has emerged as a key contributor to atherosclerosis (104, 105) and is upregulated in PLWH on ART (106). NLRP3 also plays a role in HIV-associated atherosclerosis (107) and is activated by replicating HIV in monocyte-derived macrophages (108). HIV promotes foam cell formation, with infected monocyte-derived macrophages increasing foam cells despite ART treatment (109), independent of oxLDL treatment, which synergistically increased the secretion of IL-β and IL-18. Interestingly, foam cell formation is inhibited in HIV-infected macrophages treated with ox-LDL and the NLRP3 inhibitor MCC950. Elevated levels of IL-1β are associated with endothelial dysfunction, arterial inflammation, and plaque instability, thereby sustaining residual CVD risk. These data suggest that NLRP3 may be a promising therapeutic target for HIV-associated ASCVD.

THE GUT MICROBIOME

The gut microbiome has homeostatic and pathogenic roles in immune regulation, which may directly contribute to the development and progression of ASCVD (110). Specific gut microbiota signatures have been linked to atherosclerosis progression in PLWH, such as increased Agathobacter and Ruminococcus and decreased Prevotella (111). Microbial dysbiosis drives systemic inflammation and vascular damage, highlighting therapeutic targets for CVD.

CONCLUSION

Addressing residual ASCVD risk in PLWH remains important beyond the REPRIEVE trial. This review highlights key contributors, including chronic inflammation, immune dysfunction, and clonal hematopoiesis. Taking multiple immune factors from REPRIEVE and other large cohort studies may inform new predictive models as published in smaller studies (112). Future studies should explore the impact of statins and anti-inflammatory therapies (Figure 2, see Video Abstract).

Figure 2. Targeting residual inflammation.

In REPRIEVE, pitavastatin decreased circulating LpPLA-2, oxLDL, and hs-CRP in PLWH but not other inflammatory markers (left panel). Residual risk of cardiovascular disease due to inflammation in PLWH could be due to multiple factors, including HIV reservoir, dysfunctional CD4⁺ T cells, co-infections, a leaky gut, and altered microbiome, and trained immunity (middle panel). Current therapies that reduce inflammation include statins and antiretroviral therapy (ART). Additional studies have tested anti-inflammatory medications (methotrexate, colchicine), drugs targeting cytokine receptors, and probiotics. The risk of infections has made some of these non-viable. Other targets include chemokines, chemokine receptors (maraviroc, cenicriviroc mesylate - dual CCR2/CCR5 blocker - Clinical trial #NCT05630885), and medications targeting co-infections, including hepatitis C and cytomegalovirus.

Video.

Download video file ^{(28.2MB, mp4)}

KEY POINTS.

• Chronic HIV infection is associated with pro-inflammatory N-glycan shifts, elevated anti-apolipoprotein A1 antibodies, CMV-driven CD8⁺ T cell activation, NLRP3 inflammasome activity, and gut immune dysregulation, all contributing to systemic inflammation and heightened cardiovascular risk.

• The residual risk of major cardiovascular events in PLWH on statin therapy may be driven by persistent lipid abnormalities (elevated cholesterol, triglycerides, and lipoprotein [a]), and pro-thrombotic and inflammatory pathways.

• Taking multiple immune factors from REPRIEVE may inform new predictive models as published in smaller studies.

• Potential therapeutic approaches currently being investigated include immunomodulators like methotrexate and colchicine, cytokine pathway inhibitors, JAK inhibitors, and anti-inflammatory agents like maraviroc and cenicriviroc mesylate.

• Addressing co-infections, gut microbiome imbalances, and inflammasome activation (e.g., NLRP3) through targeted therapies and probiotics may also reduce systemic inflammation and cardiovascular risk in PLWH.