B cells and atherosclerosis; A HIV perspective

Abstract

Atherosclerosis remains a leading cause of cardiovascular disease (CVD) globally, with the complex interplay of inflammation and lipid metabolism at its core. Recent evidence suggests a role of B cells in the pathogenesis of atherosclerosis; however, this relationship remains poorly understood, particularly in the context of HIV. We review the multifaceted functions of B cells in atherosclerosis, with a specific focus on HIV. Unique to atherosclerosis is the pivotal role of natural antibodies, particularly those targeting oxidized epitopes abundant on modified lipoproteins and cellular debris. B cells can exert control over cellular immune responses within atherosclerotic arteries through antigen presentation, chemokine production, cytokine production, and cell–cell interactions, actively participating in local and systemic immune responses. We explore how HIV, characterized by chronic immune activation and dysregulation, influences B cells in the context of atherosclerosis, potentially exacerbating CVD risk in persons with HIV. By examining the proatherogenic and antiatherogenic properties of B cells, we aim to deepen our understanding of how B cells influence atherosclerotic plaque development, especially within the framework of HIV. This research provides a foundation for novel B cell-targeted interventions, with the potential to mitigate inflammation-driven cardiovascular events, offering new perspectives on CVD risk management in PLWH.

Introduction

In recent years, advances in antiretroviral therapy (ART) have significantly improved the life expectancy of persons living with HIV (PLWH) (Olender et al., 2012). As a result, HIV is a manageable chronic condition (Deeks et al., 2013). However, accelerated aging is prevalent among PLWH despite ART. Multiple studies suggest that chronic inflammation contributes significantly to non-communicable diseases of aging in PLWH. This includes an increased risk of developing cardiometabolic diseases, including metabolic syndrome, atherosclerotic cardiovascular disease (ASCVD), and diabetes mellitus (Fragkou et al., 2023). These non-communicable diseases of aging are significant contributors to morbidity and mortality among PLWH, surpassing the direct effects of HIV in the era of ART (P et al., 2018).

Atherosclerosis, a chronic inflammatory condition, impacts both large and medium-sized arteries, resulting in cardiovascular diseases like ischemic heart disease, stroke, and peripheral vascular disease (Kobiyama & Ley, 2018). This pathology is primarily fueled by the interplay between oxidized low-density lipoprotein (oxLDL) and immune cells within the arterial wall (Mehu et al., 2022). Notably, the presence of (auto)immune reactivity against various autoantigens, particularly modified LDL, is also a hallmark of cardiovascular disease in humans (Inoue et al., 2001). In experimental models, this immune reactivity has been shown to significantly contribute to the progression of atherosclerotic plaques (Kobiyama & Ley, 2018; Tsimikas et al., 2001). The oxidation of LDL generates immunogenic epitopes recognized by both the innate and adaptive immune systems including T cells, B cells, NK cells, and macrophages (Galkina & Ley, 2009). Among the various immune cell subsets implicated in these processes, B cells are emerging as critical players in both cardiovascular disease (Srikakulapu & McNamara, 2017) which may overlap with B cell changes due to HIV (Moir & Fauci, 2009). In PLWH, B cell dysfunction persists even after initiation of antiretroviral therapy (Abudulai et al., 2016; Pensieroso et al., 2013). Both proatherogenic and antiatherogenic properties have been assigned to B cell subsets with different functional targets (Srikakulapu & McNamara, 2017).

This review aims to comprehensively examine the role of B cells in the development of cardiometabolic diseases, particularly among people living with HIV, as the existing studies are relatively scarce, and there are significant gaps in our understanding within this population. By synthesizing existing literature, we highlight the intricate interplay between B cells, HIV, chronic inflammation, and metabolic derangements. Furthermore, we will define the potential mechanisms through which B cells contribute to the development and progression of cardiometabolic diseases in this unique population. The elucidation of the complex interactions between B cells, HIV, and cardiometabolic diseases will not only provide insights into disease pathogenesis but will pave the way for the development of a different class of targeted therapeutic interventions that include monoclonal antibodies.

B cell Development and Differentiation

B cell development occurs primarily within the bone marrow through a multistep process. Hematopoietic stem cells (HSCs) committed to the lymphoid lineage undergo a stepwise process of differentiation and maturation to become functional B cells. This process involves several checkpoints and regulatory mechanisms to ensure the generation of a diverse repertoire of B cells capable of recognizing a wide array of antigens, while also eliminating self-reactivity (Ollila & Vihinen, 2005) (Pelanda et al., 2022)

The earliest B cell progenitors, known as pro-B cells, undergo V(D)J recombination, a process that enables the generation of diverse B cell receptor (BCR) repertoires through the rearrangement of gene segments. Successful recombination leads to the expression of a functional μ-heavy chain, resulting in the transition from the pro-B cell to the pre-B cell stage. Pre-B cells subsequently undergo selection, including pre-BCR signaling to ensure the survival of cells that have undergone productive recombination (Mårtensson et al., 2007), (Benitez et al., 2014), (Melchers, 2005). Light chain rearrangement at the pre-B cell stage creates the mature BCR, which defines the antigen specificity of the cell and marks transition to the immature B cell stage (Rastogi et al., 2022).

After the pro-B and pre-B cell stages, immature B cells migrate from the bone marrow to the spleen where they undergo final maturation through transitional B cell stages to become mature B cells (Rolink et al., 2004). (Giltiay et al., 2019). In the spleen, B cells can be classified as marginal zone (MZ) B cells, regulatory B cells, follicular B cells, activated B cells, germinal center (GC) B cells, plasma cells (short or long lived) and memory B cells (Sagaert & De Wolf-Peeters, 2003). Self-reactive B cells can also adopt an anergic B cell phenotype and fate (Cambier et al., 2007). This maturation involves the upregulation of surface molecules, including CD21 and CD23. Successful maturation leads to the generation of mature naïve B cells that express both IgM and IgD isotypes (Y. Wang et al., 2020).

As B cells originating from the bone marrow migrate to the periphery to complete maturation, they maintain surface expression of CD10, with concurrent low levels of the CD21 complement receptor (Benitez et al., 2014), (Malaspina et al., 2006). During the progression from immature/transitional B cells to naive B cells, CD21 expression increases as CD10 decreases to background and remains undetectable on mature B cells in circulation, with the exception of a minor population of “germinal center (GC) founder” B cells that can be distinguished by the co-expression of CD10 and the memory B cell marker CD27 (Bohnhorst et al., 2001). Affinity-matured B cells that exit the GC either do so as memory B cells or as antibody-secreting cells (F. J. Weisel et al., 2016). Antibody-secreting cells can also arise via extrafollicular responses, particularly in autoimmunity (Jenks et al., 2018). Short-lived plasmablasts are highly proliferative antibody-secreting cells, whereas long-lived plasma cells are not rapidly dividing and often home to the bone marrow (Manz et al., 2002). Both plasma cells and plasmablasts can be readily identified by their high levels of expression of CD38 and CD27, and CD138 (Moir & Fauci, 2017).

B cell Subsets and Function:

Following their maturation, B cells can differentiate into distinct subsets with unique phenotypic and functional properties. Classically, B cell subsets have been categorized based on surface markers, antibody isotype expression, and functional attributes (Rastogi et al., 2022). Several distinct B cell subsets have been characterized within the human bloodstream and secondary lymphoid organs. These subsets reflect various developmental stages in the transition of naive B cells into effector B cells (Vugmeyster et al., 2004). B cell definitions vary between mice and humans as outlined in Table 1.

Table 1.

Differences in B cell subsets as defined in mice and humans

B cell Subset	Functions	Mice	Humans	Refs
Pro B cells	Differentiate into pre-B cells & re-arrange immunoglobulin heavy chain genes to generate functional B cell receptor	Present in the bone marrow Markers: CD19+CD10+ CD25−	Present in the bone marrow Markers: CD19+CD10+ CD34+ CD117+	(Bertrand et al., 2001), (von Muenchow et al., 2017)
Pre-B cells	Express pre-BCR, which signals the cell to stop rearranging immunoglobulin heavy chains and start proliferating. They undergo positive and negative selection to ensure functional BCR. They differentiate into immature B cells.	Present in the bone marrow Markers: CD19+CD10+ CD25+	Present in the bone marrow Markers: CD19+CD10+ CD34−	(Bertrand et al., 2001), (Patton et al., 2014),
B-1 Cells B-1a Innate response activator (IRA) B cells B-1b	They can be activated in a T cell-independent manner mainly by carbohydrate antigens. Spontaneous IgM secretion, to natural antigens prior to exposure to immunization. Innate like, do not form memory B cells. B1 cells may have a role in homeostatic and regulation of autoimmune activity. IRA produce granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in response to lipopolysaccharides (LPS). IRA have been implicated in atherosclerosis.	Present in the peritoneal cavity and spleen B-1a Markers: IgMhi IgDlo CD19+ CD5+ CD23lo/−CD43+ CD45lo IRA Markers: [IgMhigh B220+ CD19+ CD23low CD21low CD138high CD43high VLA4high CD284+] B-1b Markers: IgMhi IgDlo CD19+ CD5− CD23lo/−CD43+CD45lo Mostly CD11b+ in the peritoneal cavity and CD9+ shared with MZB cells.	Present in low numbers, mostly in mucosal tissues B1 cell Markers: CD20+ CD27+CD43+	(Haas, 2015), (Aziz et al., 2015; Human B-1 Cells Take the Stage - PMC, n.d.), (Chiappini et al., 2015), (Rothstein et al., 2013), (Griffin et al., 2011; Yammani & Haas, 2013) (Chousterman & Swirski, 2015), (Hilgendorf et al., 2014), (Chiappini et al., 2015)
B2 cells: Follicular B cells: FOB (B2B)	FOB cells are mainly activated through T cell-dependent mechanisms by protein antigens. They undergo class switching and can produce IgA, IgG and IgE antibodies. They give rise to memory B cells and plasma cells. FOB can form germinal centers.	CD19+ CD21+ CD23hi IgM+ IgD+	CD19+ CD20+ CD23+ CD27+ CD1c+ IgM+ IgD+	(Oliver et al., 1999), (Cerutti et al., 2013; Pillai & Cariappa, 2009)
B2 cells: Marginal zone (MZB)	MZB are mainly activated through T cell-independent mechanisms by polysaccharide antigens. As such, are involved early in response to pathogens. They mainly produce IgM antibodies but can also undergo class switching. Can generate plasma cells	Present in the spleen Markers: CD19+ CD21hi CD23+/lo CD1dhi IgMhi IgDlo	Present in blood, spleen and secondary lymphoid organs. Markers: CD19+ CD20+ CD21hi CD23− CD1c+ IgMhi IgDlo	(Cerutti et al., 2013), (Pillai & Cariappa, 2009; Weill et al., 2009),
Germinal Center B cells	Participate in somatic hypermutation and class switch recombination to improve BCR affinity and change antibody isotype Compete for survival signals from T follicular helper cells Differentiate into memory B cells or plasma cells	Present in the germinal center Markers: B220+ CD19+ FAS+ GL7+	Present in the germinal center Markers: CD19+CD10+ CD38+	(Klippert et al., 2016), (Young & Brink, 2021) (Garraud et al., 2012)
Bregs	Regulate immune responses by producing IL-10 and TGF-beta. Suppress inflammation and prevent autoimmunity. Play a role in immune tolerance and tissue homeostasis.	Lack of universal markers to identify Bregs. B10: IL10-producing B cells. Located in/near MZ	Lack of universal markers to identify Bregs Makes up less than 1% of human PBMC IL10-producing memory B-regs IL10-producing transitional B-regs may also express CD19+ CD24hi CD38hi IL-21-induced Bregs may express IgM+ CD1d+ CD19+CD38+ CD147+	(Matsumura et al., 2023) (Rosser & Mauri, 2015), (Garraud et al., 2012),(Kessel et al., 2012)
Atypical Memory B cells	Reside in non-lymphoid tissues and respond to local infections Exhibit a unique combination of memory and naive features. Are expanded in chronic viral infections and autoimmune diseases.	CD21− CD27−	(~70%) CD21− CD27−	(F. Weisel & Shlomchik, 2017) (Vugmeyster et al., 2004)
IgM Memory B cells (lymphoid and non-lymphoid organs)	They contribute to early protection against previously encountered pathogens before class-switched antibodies are produced. These memory cells last for years. Produce high-affinity IgM antibodies upon re-stimulation with the same antigen.	Less common. IgM+	Less common. IgM+ CD27+	(F. Weisel & Shlomchik, 2017), (Mestas & Hughes, 2004)
Plasma cells	Produce large amounts of antibodies upon activation by antigens (T-dependent and T-independent) Have high metabolic activity and specialized protein synthesis machinery.	B220lo CD19lo CD27+, CD44+, CD93+, CD138+	CD10− CD19+/− CD20dim/– CD27hi CD38hi CD138+	(Neumann et al., 2015), (Brynjolfsson et al., 2018), (Klippert et al., 2016)
CD1c+, CD11c+ and CD8+ B cell Subsets	Respond to virus specific antigens	Lack group 1 CD1c CD11c+/−- CD11c+ are age-associated B cells in mice that appear at the peak of the humoral immune response to specific mouse viruses such as mouse CMV,	3.3% are CD1c+ B cells CD8α is found almost exclusively on T cell and NK cell subsets except in HIV-1	(Bjornson-Hooper et al., 2022) (Rubtsova et al., 2015)

B cell subsets in mice

B cell subsets have been classified based on their origin, destination, and surface marker expression. In adult mice, there are three main types of mature B lymphocytes: B-1 cells, marginal zone B cells, and follicular B cells. B-1 cells primarily arise from the fetal liver and in mice, consist of B-1a and B-1b subsets (Dorshkind & Montecino-Rodriguez, 2007). On the other hand, B-2 cells originate from the bone marrow and consist of follicular B (FOB) and marginal zone B (MZB) cells (Vale et al., 2015). B regulatory cells (Bregs) play a role in inhibiting immune responses mainly through the production of the anti-inflammatory cytokines (Y. Wang et al., 2020). A summary of the major B cell subsets that have been described in atherosclerosis in mice is provided below for context. These B cell subsets are all diverse and are further divided based on their location, activation, phenotype, and function (Table 1).

B-1 cells [CD19⁺ CD11b⁺ sIgM^hi sIgD^low]:

A distinct subset of B cells that primarily reside in the peritoneal and pleural cavities (Haas, 2015),(Martin & Kearney, 2001). They can be identified by their unusual CD11b⁺ sIgM^hi sIgD^low phenotype (Kantor & Herzenberg, 1993). Peritoneal B-1 cells are further subdivided into B-1a and B-1b (Dorshkind & Montecino-Rodriguez, 2007). B-1 cells are characterized by their self-renewing capacity, which enables them to persistently generate a population of B-1 cells. They have a significant role in the early defense against pathogens, often independent of T cells and particularly at mucosal surfaces. They are notable for their ability to produce "natural antibodies" often with low affinity that provide innate immunity against a wide range of common pathogens (Kantor & Herzenberg, 1993). Due to their unique characteristics and functions, B-1 cells are an essential component of the innate immune system and contribute to the first line of defense (Cunningham et al., 2014).

B1a cells also express CD5 and are primarily known for their self-renewal capacity, innate-like immune functions, and their propensity to produce natural antibodies, particularly IgM, in response to various antigens, including self-antigens. B1b on the other hand are characterized by their limited self-renewal ability and preferentially produce IgA antibodies, particularly in mucosal immune responses (Hardy & Hayakawa, 2001),(Berland & Wortis, 2002). The expression of CXCR4 on murine B1 cells facilitates their homing to CXCL12-rich niches within peripheral tissues (Stein & Nombela-Arrieta, 2005). Recent investigations have highlighted the pivotal role of CXCR4 in regulating the migration of B1 cells to the bone marrow. This was evidenced by two studies which demonstrated that CXCR4 deficiency led to a decrease in B1 cell population within the bone marrow, resulting in lowered levels of IgM (Döring et al., 2020; Upadhye et al., 2019). Furthermore, the absence of CXCR4 specifically in B cells of female Apoe^−/− mice was associated with increased susceptibility to atherosclerosis (Döring et al., 2020). These findings underscore the significance of CXCR4 in modulating B1 cell dynamics and its potential implications in atherosclerosis progression.

Innate response activator (IRA) B cells [IgM^high B220⁺ CD23^low CD21^low CD138^high CD43^high VLA4^high]:

These cells represent a transitional subset of B1a cells that have been described in mice. They play pivotal roles in both protective and inflammatory immune responses, particularly in the context of infections and inflammatory diseases (Chousterman & Swirski, 2015). B-1a cells migrate to the spleen in response to specific stimuli, such as pathogen-associated molecular patterns like LPS, which activate Toll-like receptor 4 (TLR4) signaling. This migration to the spleen marks the development of IRA B cells, setting them apart from other B cell subsets (Godin et al., 1993),(Wardemann et al., 2002). They express a unique set of surface markers, including CD19, B220, IgM, MHCII, CD5, CD43, CD93, CD138, VLA4, and CD284 (TLR4), making them distinguishable from other B cells (Hilgendorf et al., 2014), (Chiappini et al., 2015). Functionally, IRA B cells are notable for their production of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in response to specific triggers, particularly lipopolysaccharides (LPS) (Djoumerska-Alexieva et al., 2013). These cells have also been implicated in various diseases, including atherosclerosis. In this context, IRA B cells accumulate in secondary lymphoid organs and contribute to the inflammatory response, particularly through the production of IL-3 (Hilgendorf et al., 2014), (Chousterman & Swirski, 2015).

Follicular (FO) B cells [CD19⁺ CD23^hi IgM^hi IgD^hi]:

These are the most abundant subset of B cells in the spleen and are a subset of B2 B cells (Y. Wang et al., 2020). These B cells are essential for the formation of germinal centers (Liu & Arpin, 1997) and express high levels of IgM and IgD on the cell surface (Gray et al., 1984), (Oliver et al., 1999). Within germinal centers, B cells undergo somatic hypermutation and affinity maturation, leading to the production of high-affinity antibodies that play a crucial role in neutralizing pathogens and promoting effective immune responses (Elsner & Shlomchik, 2020).

Marginal zone B (MZB) cells [CD19⁺ CD21^hi CD23^+/lo CD1d^hi]:

A subset of B2 cells that localize to the marginal zone of the spleen in mice, where they act as a first line of defense against blood-borne pathogens (Cerutti et al., 2013). MZB cells exhibit an activated phenotype and express high levels of CD21 (complement receptor 2). Unlike FOB cells, which predominantly display mono-reactive BCRs, a significant portion of marginal zone MZB cells exhibit polyreactive BCRs capable of binding to multiple microbial molecular patterns (Janeway & Medzhitov, 2002), (Neumann et al., 2015), (Bendelac et al., 2001). Marginal zone B cells, like B1 cells, are an innate-like population of B cells that are particularly important for initiating early immune responses. After interacting with antigens, they rapidly differentiate into plasmablasts producing IgM or class-switched IgG and IgA isotypes (Puga et al., 2011), (Weill et al., 2009), (MacLennan et al., 2003). MZB cells are critical in providing protection during the initial stages of infection (Martin et al., 2001) (Cerutti et al., 2013).

Bregs:

Bregs have attracted considerable attention in recent years due to their unique immunosuppressive and anti-inflammatory functions (Rosser & Mauri, 2015). Unlike other B cells, there is a lot of heterogeneity in this subset and there are no universal markers to identify them. Bregs are specialized B cells that can secrete regulatory cytokines, such as interleukin-10 (IL-10), IL-35, and transforming growth factor β (TGF-β), and have a vital role in dampening excessive immune responses and preventing immune-related tissue damage (Rosser & Mauri, 2015). By inhibiting the activation and differentiation of pro-inflammatory T cells and promoting the expansion of regulatory T cells, through the production of TGF-β, lipopolysaccharide (LPS)-activated Breg cells can induce both apoptosis of CD4⁺ T cells (Tian et al., 2001) and anergy in CD8⁺ effector T cells (Parekh et al., 2003). Bregs help maintain immune tolerance and prevent autoimmune diseases and chronic inflammatory conditions (Evans et al., 2007), (R.-X. Wang et al., 2014) .

B cell subsets in Humans

Like mice, humans have different B cell subsets however, there is no evidence of a B1a/b cell subdivision. Masumoto and colleagues conducted an analysis involving various sorted human B cell subsets after activation with CpG, IL-2, IL-6, and IFN-α. Their findings indicated that transitional B cells (CD27^int CD38⁺) undergo differentiation into plasmablasts that secrete IL-10, which is typically linked with immune regulation.

B1 cell classification in humans is less defined and more convoluted than in mice. CD20⁺CD27⁺CD43⁺CD 70⁻ are the surface markers used to identify these cells (Griffin et al., 2011). These B1 cells can be further subdivided into secretor B1 cells (CD11b-) that secrete large amounts of IgM and orchestrator B1 cells (CD11b+) that produce both IgM and anti-inflammatory cytokine IL-10 to suppress T-cell activation (Griffin & Rothstein, 2011). B1 cells in humans produce IgM to modified phospholipids linked to atherosclerosis (Engelbertsen et al., 2015; Griffin et al., 2011). CD20⁺CD27⁺CD43⁺ B1 cells inversely correlates with coronary artery plaque burden and necrosis (Döring et al., 2020; Upadhye et al., 2019). CXCR4 might be an additional marker for identifying B1 cells that produce IgM to MDA-LDL in humans (Upadhye et al., 2019). CXCL12, also known as stromal cell-derived factor 1 (SDF-1), serves as the ligand for CXCR4 and is abundantly expressed in atherosclerotic plaques (Abi-Younes et al., 2000; Döring et al., 2014). Through the CXCL12/CXCR4 axis, B1 cells are recruited to the atherosclerotic lesions, where they can interact with other immune cells, endothelial cells, and resident macrophages, resulting in IgM production (Upadhye et al., 2019) and contributing to disease pathogenesis.

Moreover, there appears to be a correlation between CXCR4 expression on B1 cells and specific immune responses relevant to atherosclerosis. Studies have shown that higher levels of CXCR4 expression on B1 cells are associated with increased production of MDA-modified LDL-specific IgM antibodies, while inversely correlating with coronary plaque burden in humans(Upadhye et al., 2019). Although it is not possible to confirm a causal link between CXCR4 expression on B1a cells and production of IgM to MDA-LDL via regulation of trafficking to the bone marrow in humans, the associative data in mice and humans suggests a common or related mechanism. This strengthens the rationale for pursuing strategies that may increase CXCR4 expression on human B1 cells, which are primed to produce IgM to oxidized phospholipids, as a potential therapeutic target for atherosclerosis. However, in PLWH increased CXCR4 expression is unknown and but is worth studying because this is a coreceptor for HIV infection.

B2 cells develop in the bone marrow and travel to secondary lymphoid organs where they can transform into mature naïve B cells, memory B cells, or antibody-producing plasma cells (Cano & Lopera, 2013). Plasmablasts are rapidly produced in the early antibody response and further develop into plasma cells, which secrete much higher levels of antibodies, including high-affinity IgG (Meeuwsen et al., 2017). Increased plasmablasts are associated with atherosclerosis in humans (Meeuwsen et al., 2017).

Marginal zone B cells (MZB) in humans are found in the spleen, secondary lymphoid organs and they can recirculate in the blood (Weill et al., 2009).

Regulatory B cells (Bregs) in humans are also a heterogenous population of cells that can suppress the immune system and control inflammation, often through the secretion of IL-10 (Mauri & Bosma, 2012). Like mice, there are no universal markers that allow for the identification of human Bregs. Decreased serum levels of IL-10 have long been associated with human CVD, and it is hypothesized that IL-10-producing Bregs suppress plaque development (Smith et al., 2001).

Cardiometabolic Diseases in PLWH

PLWH have 1.5- 2 fold increased risk of developing CVD compared to people without HIV which is not explained by differences in traditional risk burden (A. S. V. Shah et al., 2018). HIV is associated with chronic inflammation, immune activation, and endothelial dysfunction, all of which are known contributors to ASCVD (Figure 1) (Fragkou et al., 2023). In addition to traditional risk factors which include smoking, hypertension, and dyslipidemia, co-infection with other viruses such as cytomegalovirus and microbial translocation due to reduced immune barriers in the gut after HIV infection, all contribute to inflammation, endothelial dysfunction, and the progression of atherosclerosis. Over the past few decades, considerable progress has been made in understanding the intricate relationship between immune dysregulation and the development of ASCVD. However, there the role of B cells in atherosclerosis among PLWH still needs further investigation.

Figure 1. Pathogenesis of Cardiometabolic Diseases in PLWH.

The pathogenesis of cardiometabolic diseases among PLWH is multifactorial and involves complex interactions between traditional risk factors, immune dysregulation, altered cholesterol metabolism, direct effects of HIV, dyslipidemia, gut microbial translocation and ART-related metabolic disturbances (Kearns et al., 2017), (Fragkou et al., 2023). Created with BioRender.com

Atherosclerosis as an inflammatory condition

As discussed in previous sections, atherosclerosis is a persistent inflammatory condition affecting the larger and medium-sized arteries, leading to cardiovascular diseases such as ischemic heart disease, strokes, and peripheral vascular disease (Kobiyama & Ley, 2018). Atherosclerosis is driven by the interaction between oxidized LDL and immune cells within the arterial wall (Kobiyama & Ley, 2018). The oxidation of LDL generates immunogenic epitopes recognized by both the innate and adaptive immune system (Ammirati et al., 2015). Macrophages, derived from monocytes, play a pivotal role in atherosclerosis by taking up oxidized LDL and forming foam cells, contributing to plaque formation (Shrestha et al., 2014), (Galkina & Ley, 2009). The activation of macrophages is triggered by lipid-derived danger signals, including oxidized phospholipids and cholesterol crystals, which stimulate inflammatory responses through specific receptors and signaling pathways (Hansson, 2005). Throughout this process, macrophages are stimulated by danger-associated molecular patterns derived from lipids, such as oxidized phospholipids, which promote cytokine secretion through receptors like scavenger receptor CD36 and Toll-like receptors (TLRs) (Libby, 2012). Additionally, cholesterol crystals activate the inflammasome, resulting in the production of interleukin-1β. (Tsiantoulas et al., 2015). The presence of (auto)immune reactivity against various autoantigens, particularly modified low-density lipoprotein (LDL), is a hallmark of cardiovascular disease in humans (Inoue et al., 2001). In experimental models, this immune reactivity has been shown to significantly contribute to the progression of atherosclerotic plaques (Kobiyama & Ley, 2018; Tsimikas et al., 2001).

B cells in Atherosclerosis

The role of B cells in atherosclerosis is complex and multifaceted (Ketelhuth & Hansson, 2016). While a growing body of evidence suggests that B cells play a significant role in influencing the progression of atherosclerotic plaques, some studies have shown competing effects of B cell populations on plaque formation. Furthermore, most of the studies that define B cells in atherosclerosis have been in mice, which are generally resistant to atherosclerosis. Both pro- and anti-atherosclerotic mechanisms of B cells could be driven by antibodies against oxidation-specific epitopes of LDL. IgG antibodies to ApoB100, for instance, have been suggested to promote atherosclerosis, and elevated IgE antibodies have been associated with coronary heart disease (J. Wang et al., 2011a). B1 and marginal zone B cells are recognized for their protective role against atherosclerosis, while follicular B cells and IRA B cells have been shown to contribute to the promotion of atherosclerosis (Sd et al., 2021), (Perry & McNamara, 2012).

Pro-atherogenic:

In the context of atherosclerosis, antibodies against oxidized LDL cholesterol, may promote the formation of immune complexes that activate inflammatory pathways within the arterial wall(Prasad et al., 2017; Tsimikas et al., 2001). Furthermore, B cells can also serve as antigen-presenting cells, facilitating the activation of T cells and promoting the secretion of pro-inflammatory cytokines that contribute to plaque formation and progression (Tsiantoulas et al., 2015). Depletion of B2 cells using anti-CD20 or lack of B cell-activating factor receptor (BAFFR) protected hypercholesterolemic mice against atherosclerosis (Sage et al., 2012). In a different study, anti-CD20 antibody treatment, which preferentially depleted B2 B cells, reduced atherosclerosis in atherogenic diet-fed mice. Adoptive transfer of splenic B2 B cells aggravated atherosclerosis, further highlighting the proatherogenic role of B2 B cells (Ait-Oufella et al., 2010) (Kyaw et al., 2010). In a separate study, BAFFR-deficient mice lacking mature B2 cells developed decreased atherosclerosis, again suggesting the proatherogenic role of B2 B cells (Kyaw et al., 2012a) (Nus et al., 2020). The heterogeneity within the B2 B cell population, with different subsets exhibiting diverse localization properties, activation requirements, and immunoglobulin secretion profiles, suggests that different B2 B cell subsets may have varying or even opposing roles in atherogenesis (Tsiantoulas et al., 2014) (See figure 2,3).

Figure 2: The biology of atherosclerosis.

One of the earliest events in atherosclerosis is endothelial dysfunction, which is characterized by a reduced production of nitric oxide and an increased expression of adhesion molecules, such VCAM-1, ICAM-1, and E-selectin, that promote the adhesion and transmigration of immune cells, such as monocytes and T cells, into the subendothelial space. Once in the intima, monocytes differentiate into macrophages and take up modified lipoproteins, such as oxLDL, leading to the formation of foam cells and the initiation of an inflammatory response. The recruitment and activation of immune cells, such as T cells and B cells, further exacerbate the inflammation and promote the proliferation and migration of smooth muscle cells, which contribute to the formation of a fibrous cap that encloses the lipid-rich core of the plaque. The plaque can continue to grow and become more complex, leading to the development of a vulnerable plaque that is prone to rupture or erosion, which can result in the formation of a thrombus that can obstruct blood flow and cause acute cardiovascular events. Created with using Servier Medical Art, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 3: B cells in atherosclerotic lesions of mice.

B1a and B1b cells produce IgM antibodies against oxidation-specific epitopes, which helps to clear apoptotic cells and suppress CD4 and CD8 T cells. Regulatory B cells secrete IL-10, which influences T regulatory cells and inhibits mitochondrial reactive oxygen species mediated activation of endothelial cells. Innate response activator (IRA) B cells produce high amounts of granulocyte–macrophage colony-stimulating factor, which activates dendritic cells and acts atherogenic. The follicular B2 cells may act proatherogenic depending on the state of inflammation and the local inflammatory microenvironment, while the marginal zone B2 cells are involved in cholesterol metabolism and act atheroprotective by taking up oxidized LDL.

¹Ait-Oufella et al., 2010; ² Hilgendorf et al., 2014; ³ Kyaw et al., 2011, 2012; ⁴ Mauri & Bosma, 2012. Created with BioRender.com

For example, a subset of B1 cells, IRA B cells promote atherosclerosis, their depletion in mice leads to decreased interferon-gamma-secreting CD4⁺ T cells, reduced anti-oxLDL IgG2c-specific antibodies, and reduced atherosclerosis (Hilgendorf et al., 2014) (Moir & Fauci, 2008). Gene expression studies and genome-wide association studies have identified critical genes involved in B cell survival, proliferation, or activation status as key drivers of coronary heart disease, suggesting the importance of B cells in human atherosclerosis (Huan et al., 2013).

Atheroprotective:

Immunization against LDL and other atherosclerosis-related antigens has been shown to have atheroprotective effects in an animal model (P. K. Shah et al., 2005). Partial (Caligiuri et al., 2002) and complete (Major et al., 2002) B cell depletion in Apoe^−/− and LDL receptor-deficient (Ldlr^−/−) mice respectively results in enhanced atherosclerotic plaque formation, supporting a protective role of B cells in atherosclerosis. B1 cells have emerged as atheroprotective players due to their unique ability to produce natural IgM antibodies that bind apoptotic cells and oxLDL (Kyaw et al., 2011). Natural IgM antibodies have been shown to neutralize the proinflammatory effects of oxLDL, inhibit foam cell formation, and promote the clearance of apoptotic cells. Splenectomy of Apoe^−/− mice led to a reduction in B1a cells and plasma IgM titers, and adoptive transfer of peritoneal B1a cells reduced atherosclerosis (Kyaw et al., 2011). Epidemiological data further support the atheroprotective capacity of natural IgM, as anti-oxLDL-specific IgM antibodies have been inversely associated with cardiovascular disease (Kaveri et al., 2012). This mechanism, involving the immune response to oxidation-specific epitopes generated during hypercholesterolemia, triggers atheroprotective immunity, including the formation of germinal centers and increased antibody-secreting cells. Strategies promoting the expansion of atheroprotective natural IgM antibodies may be beneficial in human atherosclerosis (Tsiantoulas et al., 2014) (Kaveri et al., 2012). B-regulatory cells (B-regs) have been shown to exhibit anti-inflammatory properties by suppressing T cell responses and promoting the generation of regulatory T cells. Adoptive transfer of regulatory B cells reduced inflammation and atherosclerosis in mice, using an IL-10-dependent mechanism (Mauri & Bosma, 2012).

In summary, B cells traditionally recognized for their role in antibody production and humoral immunity, exhibit diverse functions beyond their well-established role in the adaptive immune response (Ollila & Vihinen, 2005). They can be atherogenic or atheroprotective as depicted in Figure 3. Despite a long-known association with atherosclerosis, B cells and antibodies have not always been a research focus (Sage & Mallat, 2014). In the context of HIV infection, B cells have been implicated in several facets of disease pathogenesis, including viral reservoir establishment, chronic immune activation, and dysregulation of the immune system (Moir & Fauci, 2017), (Moir et al., 2010). However, there is paucity of data on the role of B cells in ASCVD among PLWH.

Interaction of B cells and other immune cells in atherosclerosis

Follicular B2 cells can act as antigen-presenting cells (APCs) via MHC II to T cells, although their antigen-presenting abilities are limited compared to traditional APCs like DCs (A. S. V. Shah et al., 2018). However, B cells' ability to present antigens is essential for the interaction between B cells and their cognate T follicular helper (TFH) cells in germinal center reactions (Pillai & Cariappa, 2009). The interaction between B cells and T cells is critical in the initiation and progression of atherosclerosis as this promotes B cell maturation and class switching to IgE and IgG antibodies (Mangge et al., 2020; Packard et al., 2009).Activated T cells release cytokines that activate B cells and promote their differentiation into antibody-secreting cells(Charles A Janeway et al., 2001). These antibodies can then bind to OxLDL, leading to the formation of immune complexes that can activate macrophages and promote foam cell formation(Hansson & Hermansson, 2011) . Moreover, macrophages play a crucial role in the pathogenesis of atherosclerosis. They can take up oxidized LDL and transform into foam cells, which contribute to the formation of fatty streaks and atherosclerotic plaques(Moore et al., 2013). B cells can interact with macrophages through the production of proinflammatory cytokines and IgM antibodies that can activate macrophages and promote foam cell formation(Kyaw et al., 2011; Mangge et al., 2020). When IgE binds to FcεRI on mast cells, it can trigger the release of proinflammatory cytokines such as IL-6 and interferon-γ (J. Wang et al., 2011b; Q. Wang et al., 2019). This can contribute to the inflammatory response within the plaque and potentially lead to destabilization that is associated with clinical end points (Mangge et al., 2020).

As previously discussed atheroprotective TLR4-expressing B1a and B1b cells in mice can produce IgM antibodies against oxidation-specific epitopes, which can aid in the clearance of apoptotic cells (B1a and B1b cells) and suppress CD4 and CD8 T cells in atherosclerotic lesions. In addition, regulatory B cells secrete IL-10 that influences T regulatory cells and may be involved in TGF-ß1-mediated clearance of apoptotic cells. Furthermore, IL-35 secretion inhibits mitochondrial reactive oxygen species mediated activation of endothelial cells, suggesting a potential role for regulatory B cells in modulating the inflammatory response in atherosclerosis(Mangge et al., 2020).

Changes in B cells with HIV

The presence of chronic HIV viremia results in the expansion of various abnormal B cell subpopulations, including immature transitional, hyperactivated, and exhausted B cells (Moir, Ho, et al., 2008; Moir & Fauci, 2009, 2017). This collective effect likely contributes to different aspects of B cell dysfunction in people living with HIV(Abudulai et al., 2016; Moir, Ho, et al., 2008). HIV infection is known to be associated with a wide array of B cell aberrations, many of which are closely linked to variations in the frequencies of different B cell subpopulations(Abudulai et al., 2016; Cagigi et al., 2010; Moir & Fauci, 2008).

The majority of studies pertaining to these B cell populations have primarily centered on B cells isolated from peripheral blood, making it a pivotal focus area for understanding the immunological changes in HIV disease. (Moir & Fauci, 2008). B cells in the peripheral blood can be identified by the expression of CD19 (Vallejo et al., 2022). In PLWH, six subsets of CD19⁺ B cells have been defined based on the expression of CD10, CD20, CD21, and CD27 shown in Table 3 (Moir et al., 2010), (Boliar et al., 2012). In healthy individuals, the subpopulation of immature/transitional B cells expresses CD10 but lacks CD27 expression. The frequency of these B cells substantially increases in various immune deficiency settings, including HIV infection. In active HIV disease, immature/transitional B cells can account for over 30% of peripheral blood B cells, compared to approximately 10% in healthy individuals. Furthermore, this subpopulation can be subdivided into less immature (CD21^hi/CD10⁺) and more immature (CD21^lo/CD10⁻) B cells. The latter is rarely observed in the blood of healthy individuals but is prevalent in persons living with HIV with advanced disease (Malaspina et al., 2006),(Moir, Ho, et al., 2008).

Table 3.

Summary of changes in peripheral blood B cells in people living with HIV (in Early and chronic viremia).

B cell Sub Population	Phenotype	Changes in HIV	References
Immature transitional B cells	CD10++ CD21lo CD24+ CD27−	PWH with T-cell lymphopenia have increased proportions of immature and transitional B cells	(Malaspina et al., 2006), (Malaspina et al., 2007),(Ho et al., 2006)
immature B cells	CD10+ CD21lo CD27+	Higher proportions with HIV viremia	(Moir et al., 2001),(Moir et al., 2004)
Naïve Mature B cells	CD10− CD21hi CD27- CD38+/−	Decreased in chronic HIV infection	(Moir et al., 2010), (Moir, Ho, et al., 2008), (Boliar et al., 2012)
Resting Memory B cells	CD10− CD21hi CD27+ CD38+	Decreased in chronic HIV infection, Increased early with HIV viremia	(Moir & Fauci, 2017),(De Milito, 2004), (Moir, Malaspina, et al., 2008)
Exhausted tissue-like Memory B cells	CD10− CD21lo CD27−	Increased in association with Chronic HIV Viremia	(Moir & Fauci, 2009), (De Milito et al., 2001), (Moir, Ho, et al., 2008)
Short-lived Plasmablasts	CD10− CD19+ CD20− CD21lo CD27++ Ki-67+	Increased early with HIV viremia	(Moir et al., 2010), (Buckner et al., 2013)

A study involving 115 participants reported that within the resting/memory B cell group, a subgroup known as germinal-founder B cells (CD19⁺CD10⁺CD21^hiCD27⁺) can constitute approximately 1.4% to 1.5% of the total B cell population (Moir et al., 2010) compared to approximately 0.6% reported in healthy individuals(Béniguel et al., 2004). The germinal-founder B cells have reduced expression of CD25 induced by mitogenic stimulation (Malaspina et al., 2006). In early and chronic viremia, both the relative proportion and absolute counts of unswitched (IgM⁺) and/or switched memory B cells (IgG⁺) are diminished within the peripheral bloodstream (Moir et al., 2010).

Current evidence suggests that tissue-like memory B cells, found in the peripheral blood of individuals with ongoing HIV viremia, constitute an exhausted B cell subgroup. These B cells exhibit signs of functional exhaustion, similar to what is observed in virus-specific T cells (Moir & Fauci, 2008). This exhaustion is characterized by a loss of proliferative capacity and effector function, and decreased immunoglobulin diversification. Furthermore, tissue-like memory B cells that have undergone fewer cell divisions in vivo, potentially due to the overexpression of inhibitory receptors that impede further cell division. Interestingly, despite their exhaustion, tissue-like memory B cells are enriched for HIV-specific responses, much like their exhausted virus-specific T-cell counterparts. This phenomenon may hinder the efficiency of the antibody response against HIV in PLWH, as B cells with functional limitations are more likely to mount HIV-specific responses. (Moir & Fauci, 2009), (Moir et al., 2010), (Moir & Fauci, 2017).

Direct Effects of HIV Viremia on B cell Sub-populations

HIV infection on and off ART gives rise to a variety of immunological abnormalities, stemming from both direct and indirect consequences of viral attachment and replication. In the absence of ART, HIV infection eventually culminates in a significant state of immunodeficiency (Fauci, 1996) (Grossman et al., 2002). HIV is known to primarily target CD4⁺ T cells, however, its impact extends beyond these cells, affecting various components of the immune system (Grossman et al., 2002). One notable consequence is the impairment of B cell responses during HIV infection due to the disruption of the interaction between T cells and B cells in germinal centers (Cagigi et al., 2010). Moreover, recent research suggests that HIV-specific B cells may develop directly from immature or transitional B cells independently of T-cell assistance, possibly with an elevated level of poly/autoreactivity. (Saifi & Wysocki, 2015). Alterations that occur in the various B cell compartments of persons living with HIV are summarized (Figure 4).

Figure 4. Direct and indirect effects of HIV Viremia on B cell Sub-populations.

Direct effects (Left Panel): HIV virions and viral proteins interact with B cells. Complement-bound HIV virions engage B cells via the CD21 receptor, promoting virus dissemination and enhancing B cell depletion through apoptosis. Additionally, the binding of HIV virions or gp120 triggers B cells to release inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The diffusion of secreted Nef from HIV replication sites into B cells suppresses their ability to undergo class switch recombination. Notably, HIV-infected macrophages release factors, including some Nef-dependent factors like ferritin, that stimulate B cells. Indirect effects (Right Panel): These effects stem from HIV-induced immune-cell activation and CD4⁺ T-cell depletion. Increased serum IL-7 is associated with CD4⁺ T-cell lymphopenia, greater B cell immaturity, and diminished responses to antigens. Various systemic mediators of immune-cell activation and increased cell turnover are proposed, including lipopolysaccharide (LPS), B cell-activating factor (BAFF), TNF, interferon-α (IFNα), IL-6, and IL-10. IFN-stimulated genes are strongly induced in B cells of HIV-viremic individuals due to chronic immune-cell activation. Created with BioRender.com

Persistent HIV viremia leads to the proliferation of various B cell subgroups, characterized by diminished CD21 expression and heightened immunoglobulin secretion (Moir et al., 2001), believed to underlie multiple B cell abnormalities linked to ongoing HIV replication (Appay & Sauce, 2016), (Malaspina et al., 2003), including hypergammaglobulinemia (Sneller & Lane, 1993), (De Milito et al., 2004). These include autoreactive-prone CD21^loCD27⁺ memory B cells, CD20^loCD21^loCD27^hi Ki-67⁺ plasmablasts with short-lived activity, and memory B cells resembling tissue-resident cells (Moir et al., 2010) (Moir & Fauci, 2017). The tissue-resident-like memory B cells exhibit reduced CD21 expression and a lack of CD27 expression, which are indicative of exhaustion induced by HIV infection. (Moir & Fauci, 2009), (Moir & Fauci, 2017). Of note, there is considerable heterogeneity in CD21^lo cells outside of HIV, which also include antibody secreting cell (ASC) precursors (Meffre & O’Connor, 2019)

HIV proteins, such as gp120 and Nef, have also been proposed to act as direct or indirect activators of B cells, with mechanisms that are still largely speculative. Gp120's binding to C-type lectins on B cells can induce immunoglobulin class switching and increased expression of the activation-induced cytidine deaminase (Rieckmann et al., 1991). Nef, on the other hand, may have divergent effects on B cells, inhibiting immunoglobulin class switching while indirectly promoting polyclonal B cell activation and increasing CD4⁺ T-cell permissiveness to HIV infection (Swingler et al., 2003), (Swingler et al., 2008) .

Indirect Effects of HIV Viremia on B cell Sub-populations

In PLWH, a wide range of functional and dysfunctional phenotypes of B cells have been documented. The factors contributing to immune-cell hyperactivation in individuals with HIV-viremia remain a subject of research and debate. B cell dysfunctions are often linked to heightened B cell activity triggered by continuous viral replication and dysregulation of the Fas apoptotic pathway through the overexpression of the Fas cell surface death receptor (CD95) (Titanji et al., 2005a), (Moir, Ho, et al., 2008), (De Milito, 2004), (De Milito et al., 2001).

Upregulation of CD95 and loss of CD21 may serve as independent markers of B cell dysfunction among PLWH. Several cytokines and growth factors, including interferon-α (IFNα), tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-10, CD40 ligand, and B cell-activating factor (BAFF), have been suggested to trigger the activation of B cells in HIV-viremic individuals (Aukrust et al., 1999), (Moir & Fauci, 2017) (Mandl et al., 2008), (Weimer et al., 1998). These factors are believed to be associated with B cell hyperactivation due to their increased serum levels during HIV infection (Moir & Fauci, 2009). Moreover, B cell dysfunction in the context of HIV is characterized by several additional abnormalities, including hypergammaglobulinemia and increased expression of activation markers such as CD38, CD70, CD71, and CD86, along with reduced expression of CD22, CD25, BAFF-R, and LAIR-1 (Moir, Ho, et al., 2008), (Titanji et al., 2005a), (Malaspina et al., 2006) (Table 2 for function). These abnormalities are associated with the expansion of immature B cells and a higher incidence of B cell lymphomas, often accompanied by increased expression of cytokines like IL-6 and IL-10. (Malaspina et al., 2006), (Martínez-Maza & Breen, 2002).

Table 2:

Summary of key markers and their functions (GeneCards - Human Genes ∣ Gene Database ∣ Gene Search, n.d.)

Marker	Function
CD22	plays a role in the negative regulation of the B cell receptor signaling pathway and the regulation of endocytosis.
CD25	Binds to interleukin-2 (IL-2) thus facilitating T-cell activation, proliferation, and differentiation into effector T cells.
BAFF-R	Regulates B cell survival, development, and antibody production.
LAIR-1	Involved in maintaining immune tolerance by inhibiting the activation of T cells, B cells, and other immune cells.
CD9	Participates in the regulation of membrane dynamics and signal transduction, impacting processes such as fertilization, immune response, and cancer metastasis.
CD10	It is involved in the modulation of the local concentration of bioactive peptides and, therefore, influence immune cell interactions.
CD11b	Leukocyte adhesion and it is part of the inflammatory response by promoting the migration of immune cells to inflamed tissues.
CD11c	It mediates cell-cell interaction during inflammatory responses.
CD19	Decreases the threshold for activation of downstream signaling pathways and for triggering B cell responses to antigens.
CD20	Plays a role in the development, differentiation, and activation of B-lymphocyte
CD21	B cell activation and formation of immune memory.
CD23	Regulation of IgE, involved in antigen presentation and regulation of inflammation.
CD1d	Facilitates the presentation of lipid antigens and influencing immune responses through the activation of natural killer T-cells.
CD1c	Antigen-presentation.
CD38	Plays a role in nicotinamide adenine dinucleotide (NAD+) metabolism, immune regulation and cell adhesion.
CD43	Immune cell adhesion, migration, and regulation of immune responses.
CD44	Participates in the activation, recirculation and homing of T-lymphocytes, hematopoiesis, inflammation, and response to bacterial infection.
CD45	Immune cell activation and regulation.
CD93	Complement system interaction, Cell adhesion and migration and regulation of immune responses
CD138	Mediates the adhesion of immune cells to the endothelium, facilitating their recruitment to sites of inflammation.
CD147	Regulation of immune responses. It may influence T-cell activation, cytokine production, and leukocyte migration.

IFN-α has been implicated in B cell hyperactivation, and it is suggested that plasmacytoid dendritic cells (pDCs) might be responsible for its increased production in chronically HIV-viremic individuals (Diop et al., 2008). Bacterial lipopolysaccharide (LPS) has also been proposed as a potential activator of B cells, likely through indirect mechanisms involving the induction of pro-inflammatory cytokines like TNF and IFN-α, as human B cells do not express LPS receptors (Brenchley et al., 2006). During the initial stages of HIV infection, viremic individuals may exhibit a substantial elevation in the proportion of IgG⁺ plasmablasts within the peripheral blood, constituting a significant portion, potentially exceeding 50%, of the total circulating B cells. These plasmablasts diminish in the chronic phase of HIV viremia. It is worth noting that a large population of these plasmablasts are not HIV-specific (Buckner et al., 2013) (Moir et al., 2010).

BAFF, APRIL, HIV-1 infection, autoimmunity, and atherosclerosis.

The TNF-family member BAFF and its analog APRIL (A Proliferation-Inducing Ligand) have been shown to be critical regulators of B cell homeostasis (Hahne et al., 1998; Schneider, 2005). BAFF is essential for the survival of mature B cells, specifically, B2 cells (Mackay & Browning, 2002) while APRIL has been shown to promote the survival of plasma cells and memory B cells (Schneider, 2005). Three receptors are responsible for mediating biological activities of BAFF, namely the BAFF-receptor (BAFF-R; TNFRSF13C), transmembrane activator-calcium modulator and cyclophilin ligand interactor (TACI; TNFRSF13B), and B cell maturation antigen (BCMA; TNFRSF17)(Brink, 2006). Mature B2 cells are significantly reduced in mice with a genetically disrupted BAFF-R gene and a spontaneous mutation in the BAFF-R gene, while B1a cells remain unaffected (Kyaw et al., 2012b; Sasaki et al., 2004). Excess BAFF has been reported in PLWH and is linked to viral factors, specifically Nef, and occurs simultaneously with indicators of inflammation, such as components of microbial translocation (Chagnon-Choquet et al., 2015). HIV-1 infection is associated with the dysregulation of the B cell compartments, with increased MZ precursor-like (MZp) B cells which is thought to be due in part to the overproduction of BAFF (Aranguren et al., 2022; Gomez et al., 2015; Moir & Fauci, 2017; Titanji et al., 2005b). Similar findings of excess BAFF correlated with B cell compartment dysregulation and hyperglobulinemia with increased levels of MZ B cells have been reported in PLWH female sex workers from Benin, macaques with SIV, and HIV-transgenic mice (Poudrier et al., 2001, 2015; Sabourin-Poirier et al., 2016). These observations indicate that elevated levels of BAFF and abnormal MZ populations are a feature of the inflammatory response in the context of HIV. This dysregulation of BAFF is thought to correlate with subclinical atherosclerosis (Aranguren et al., 2022).

APRIL on the other hand has been shown to have specific atheroprotective effects. A study by Inoue et al found that overexpression of APRIL in mice resulted in decreased atherosclerotic lesion size and decreased pro-inflammatory cytokine production (Inoue et al., 2001). APRIL has also been shown to induce Breg differentiation, which can help to control inflammation and inhibit atherosclerosis (Fehres et al., 2019; Hua et al., 2016). A study by Moens et al, found that APRIL overexpression led to a significant increase in total plasma IgM levels, specific IgM antibodies against OxLDL, and a concomitant increase in plaque deposition of IgM, which correlated with a significant increase in B1a lymphocytes. While the increase did not affect lesion size or stage, the study observed phenotypical changes of the atherosclerotic lesion, with increases in smooth muscle cell numbers accompanied by an unchanged macrophage content (Bernelot Moens et al., 2016).

A study by the Canadian HIV and Aging Cohort Study found that elevated levels of BAFF in PLWH were linked to a higher risk of atherosclerosis and its risk factors, while APRIL levels were negatively correlated (Aranguren et al., 2022). In vitro experiments showed that APRIL could modulate the Breg profile of MZp, which was dampened by BAFF (Doyon-Laliberté et al., 2022). These findings suggest that modulating levels of BAFF and/or APRIL could be a potential treatment target for CVD in PLWH.

PLWH have elevated levels of BAFF, which is associated with the production of autoantibodies (Doyon-Laliberté et al., 2023). These autoantibodies may contribute to the development of atherosclerosis by targeting self-antigens. Autoimmunity has been linked to the development of atherosclerosis, and the presence of autoantibodies in atherosclerotic plaques has been well documented (Hulthe, 2004; Palinski et al., 1995; Salonen et al., 1992; Tsimikas et al., 2001). Some cross-sectional studies suggest that autoantibodies to oxidized LDL present in atherosclerotic plaques are associated with plaque instability (Inoue et al., 2001; Nishi et al., 2002). The excess BAFF in autoimmune patients may contribute to the production of these autoantibodies, which can affect their risk of developing ASCVD.

Conclusion

HIV is linked to persistent inflammation, immune activation, and endothelial dysfunction, all recognized contributors to ASCVD. The immune system, crucial for maintaining balance in the body, can undergo dysregulation in the presence of ongoing HIV infection, resulting in changes to immune cell populations and their functionalities. In PLWH, B cells, integral components of the adaptive immune system, may play a role in ASCVD development and progression.

Beyond their conventional role in antibody production, B cells exhibit diverse immune regulatory functions such as antigen presentation, cytokine generation, and modulation of T-cell responses. Recent findings propose that B cells can impact ASCVD through mechanisms extending beyond their typical antibody-related actions. These mechanisms involve the presentation of self-antigens, production of pro-inflammatory cytokines, and interactions with other immune cells. Collectively, these processes contribute to chronic inflammation, endothelial dysfunction, and atherosclerosis.

The intricate relationship between B cells and ASCVD becomes even more complex in the context of HIV infection. HIV-related immune dysregulation, marked by abnormal immune activation and persistent inflammation, significantly influences B cell stability and function. The ongoing battle of the immune system against HIV and other pathogens can exhaust B cells, disrupting their regulatory capabilities. This exhaustion leads to dysbiosis characterized by altered clearance of HIV and other pathogens, further intensifying the pro-inflammatory environment conducive to the development of ASCVD.

Understanding these intricate interactions involving HIV, the immune system, and B cells is vital for devising strategies to mitigate the cardiovascular risks associated with HIV infection. Ongoing research in this area holds the potential to unveil novel therapeutic interventions aimed at enhancing the cardiovascular health of individuals living with HIV.

Box 1. B cells in HIV infection and cardiovascular disease.

Summary

• B cells, through cytokine secretion and antigen presentation, can influence inflammation and immune cell recruitment within atherosclerotic plaques.

• There is a complex and bidirectional interaction between B cells and HIV.

• The role of B cells in cardiometabolic disease among PLWH has been understudied.

• Chronic inflammation in the setting of HIV reciprocally influences B cell function and distribution, potentially amplifying ASCVD.

Possible mechanisms

• HIV infection contributes to immune dysregulation, which in turn exacerbates the proinflammatory milieu associated with cardiometabolic diseases.

• HIV infection accelerates immune senescence, characterized by immune cell exhaustion and decreased functionality. B cell senescence in HIV may contribute to ASCVD.

• B cells can contribute to autoimmune responses and the production of autoantibodies in HIV infection. In PLWH, an increase in atherogenic B cells may be important in disease pathogenesis.

• B cells, especially memory B cells, play a role in maintaining immune memory. Their dysfunction could compromise immune surveillance against both HIV and other pathogens, contributing to cardiometabolic disease susceptibility.

• Alterations in the function or frequency of Bregs.

• HIV-associated B cell dysfunction could lead to disturbances in metabolic homeostasis, potentially exacerbating insulin resistance and dyslipidemia, key factors in cardiometabolic disease development.

Future studies

1. Deep phenotyping of B cell subsets in PLWH with and without cardiometabolic disease

   • Advanced techniques including multiparameter flow cytometry and single-cell RNA sequencing techniques to study functional changes in B cells during HIV infection and their potential role in atherosclerosis.
   • Exploring the role of autoantibodies in cardiovascular disease in PLWH.
   • Study B cell subsets in tissue compartments and understand their functional role in the context of the tissues that they are resident.

2. Exploring the role of B cells in cholesterol metabolism among PLWH

3. Understanding metabolic dysregulation of B cell function and studying ways to reverse this to improve function and downstream effects.

Abbreviations

APRIL

A proliferation–inducing ligand

ART

Antiretroviral therapy

BCR

B cell receptor

BAFFR

B-cell–activating factor receptor

ASCVD

Atherosclerotic cardiovascular disease

CVD

cardiovascular disease

GC

Germinal Center

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.