The Journal of Infectious Diseases SUPPLEMENT ARTICLE
Cardiovascular Disease, Statins, and HIV Allison Ross Eckard,1 Eric G. Meissner,1 Inderjit Singh,1 and Grace A. McComsey2 1
Medical University of South Carolina, Charleston; and 2Case Western Reserve University, Cleveland, Ohio
Human immunodeficiency virus (HIV)–infected patients are at an increased risk of serious, non–AIDS-defining comorbidities, even in the setting of viral suppression with combination antiretroviral therapy. This increased risk is due in part to immune dysfunction and heightened inflammation and immune activation associated with chronic HIV infection. Statins have wide-reaching immunomodulatory effects, and their use in the HIV-infected population may be of particular benefit. In this article, we review the pathogenesis of increased inflammation during HIV infection and how it contributes to the risk of cardiovascular disease among HIV-infected individuals. We then we review the immunomodulatory effects of statins and how they may attenuate the risk of cardiovascular disease and other comorbidities in this unique patient population. Keywords. HIV; statins; hydroxy-3-methylglutaryl coenzyme A reductase inhibitors; cardiovascular disease; inflammation; immune activation.
Early, sustained viral suppression with combination antiretroviral therapy (cART) is now considered standard of care for human immunodeficiency virus (HIV) infection, as compelling data have shown that this approach reduces serious events, slows the progression of HIV disease, and decreases mortality [1, 2]. Even in the context of long-term viral suppression, however, HIV-infected individuals are still at an increased risk, compared with the general population, of developing serious non–AIDS-defining comorbidities, including cardiovascular disease (CVD), osteoporosis, neurocognitive impairment, and malignancies. Both direct and indirect effects of chronic HIV infection cause global immune dysfunction, including increased inflammation, immune activation, and immunosenescence, which contribute to the development of these comorbidities. Until the ultimate goal of HIV eradication is achieved, adjuvant therapies to cART aimed at further reducing inflammation is of paramount importance. Statins, hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, possess widereaching immunomodulatory effects, in addition to their potent lipid level–lowering properties, making them particularly attractive for study during HIV infection. In this review, we will first discuss the predominant mechanisms by which HIV may enhance inflammation and how this contributes to the pathogenesis of CVD and other comorbidities during HIV infection. Next, we review the immunomodulatory effects of statins and how they may attenuate the risk of CVD and other comorbidities in this unique patient population.
Correspondence: A. R. Eckard, Divisions of Infectious Diseases, Departments of Medicine and Pediatrics, Medical University of South Carolina, 135 Rutledge Ave, Charleston, SC 29425 ([email protected]). The Journal of Infectious Diseases® 2016;214(S2):S83–92 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/infdis/jiw288
INFLAMMATION IN COMBINATION ANTIRETROVIRAL–TREATED HIV INFECTION
Given the ongoing viral replication and CD4+ T-cell depletion in untreated HIV infection, the presence of increased inflammation is perhaps expected. Arguably, however, a sustained increase despite viral suppression with cART is perhaps less mechanistically apparent. Identification of factors driving inflammation during combination antiretroviral–treated chronic HIV infection is imperative when considering available and novel therapeutic approaches for outcome modulation. Here, we briefly review several factors potentially subject to modulation by statin therapy; these and other factors are covered in greater depth in additional articles within this supplement. Host-Virus Interaction
While modern cART efficiently suppresses HIV replication below the limit of detection in blood, promotes CD4+ T-cell recovery and stability, and decreases levels of inflammatory and immune activation markers [3, 4], current evidence suggests that viral replication persists, likely within lymphoid organs, through cell-to-cell transmission, and/or through homeostatic proliferation [5–7]. Importantly, many markers of inflammation and immune activation are relatively nonspecific, and the precise events driving their production can be challenging to ascertain. However, this subdetectable viral replication likely contributes in part to the increased inflammation in treated HIV infection. Likewise, the residual impact of CD4+ T-cell depletion during acute and untreated HIV infection can persist, despite subsequent cART-induced viral suppression. For example, a significant depletion of gut-associated lymphoid tissue occurs during acute infection, which never fully recovers even with prolonged treatment [8–10]. This permanent alteration of gut immunity and integrity allows an increase in microbial translocation. The microbes themselves and their products (eg, lipopolysaccharide, Statins and HIV
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a component of the cell wall of gram-negative bacteria) circulate in the plasma, bind to and upregulate various receptors, and are associated with markers of immune activation [11–14]. In fact, plasma gut epithelial barrier integrity markers independently predict mortality, even after adjustment for CD4+ T-cell count, in individuals with treated HIV infection and a history of AIDS [13]. Finally, in some patients, deemed immune nonresponders, the CD4+ T-cell count does not rise to near-normal levels despite prolonged viral suppression [15, 16]. These patients have higher levels of inflammation and immune activation markers, with presumably comparable degrees of subdetectable viral persistence, implicating a permanent residual impact of host immunity that may be due to thymic fibrosis, lymphoid organ fibrosis, irreversible loss of mucosal immunity, T-cell exhaustion, or other mechanisms [17–23]. Antiretroviral Drug Effects
While modern cART regimens exhibit improved safety, improved tolerability, and a reduction in side effects relative to their predecessors, cART medications themselves may still have an impact on inflammation. An example is the use of protease inhibitors (PIs), which may contribute both directly and indirectly to immune dysfunction and inflammation during HIV infection. PIs have been associated with dyslipidemia and metabolic derangements that then contribute in a complicated interplay to affect inflammation and immune activation, as discussed in greater depth by Koethe et al elsewhere in this supplement [24]. PIs have also been shown to trigger premature senescence in endothelial cells and circulating peripheral blood mononuclear cells (PBMCs) of PI-treated HIV-infected patients [25]. However, it should be noted that newer PIs have not demonstrated a clear association with inflammation when compared to other non-PI therapies [26]. Similarly, integrase inhibitors show a broadly neutral effect on lipids, and there is some evidence to suggest that they may cause a modest decline in inflammation and immune activation [26, 27]. Comorbid Conditions
Increased inflammation in combination antiretroviral–treated patients with HIV infection may also be related to comorbid conditions, which tend to occur frequently in HIV-infected individuals. The high incidences of smoking, diabetes, dyslipidemia, and increased visceral adiposity may contribute to inflammation and immune activation independent of and/or as a result of HIV infection [28, 29]. A clear example that was recently described is the effect of oxidized low-density lipoprotein (oxLDL) cholesterol on monocyte activation. oxLDL cholesterol is a proinflammatory form of LDL cholesterol that is often found within atheromatous plaques and contributes to the generation of foam cells, an integral step in instigating an acute coronary event (see below). Zidar et al showed that HIV-infected patients have both increased plasma levels of S84
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oxLDL, as well as increased monocyte expression of oxLDL receptors [30]. Plasma oxLDL levels were also correlated with markers of monocyte activation, suggesting that increased oxLDL levels serve as a driver of monocyte immune activation during HIV infection [30]. INFLAMMATION IN THE PATHOGENESIS OF CVD AND OTHER COMORBIDITIES IN HIV-INFECTED INDIVIDUALS
Early epidemiologic studies suggested that antiretroviral drugs, especially PIs, were the primary cause of the increased risk of myocardial infarction seen in the HIV-infected population [31], owing to their well-recognized lipid and metabolic complications, which directly contribute to CVD risk. However, subsequent studies have demonstrated that HIV infection itself is independently associated with an increased risk of CVD [32–34], and despite effective viral suppression with cART, atherosclerotic CVD events, such as myocardial infarction and ischemic stroke, still occur more commonly in HIV-infected patients as compared to the general population [35, 36]. The vast amount of evidence that supports the fact that inflammation and immune activation are strongly linked to the development of CVD in the general population and in HIVinfected individuals is beyond the scope of this review but was reviewed extensively in a previous supplement of The Journal of Infectious Diseases [37, 38]. Briefly, inflammation is thought to be critical in the development of CVD at all stages [39], and equally important, both innate and adaptive immunity play integral roles. Moreover, the endothelium is a biologically active organ that becomes activated in response to injury and inflammatory mediators (including elevated circulating levels of oxLDL cholesterol [40]), causing upregulation of cellular adhesion molecules, expression of inflammatory cytokines, monocyte recruitment into the intimal space, and differentiation of monocytes into macrophages that engulf oxLDL cholesterol, producing foam cells that aggregate to form a fatty streak covered by a fibrous cap. Signaling between macrophages and T cells can promote release of matrix-degrading enzymes known as matrix metalloproteinases (MMPs), which destroy collagen within the fibrous cap, making it unstable and prone to rupture. This leads to an acute coronary event [41]. IMMUNOMODULATORY PROPERTIES OF STATINS
Statins are a class of prescription drugs that inhibit the rate-limiting enzyme, HMG-CoA reductase, in the mevalonate pathway for the synthesis of cholesterol (Figure 1). They bind to HMGCoA reductase at nanomolar concentrations as competitive inhibitors and replace the natural substrate, HMG-CoA [42]. Statins are well known for their cholesterol level–lowering effects in both plasma and cell membranes and, accordingly, their use as primary and secondary CVD prevention [43, 44]. However, statins also have wide-reaching immunomodulatory
Figure 1. Cholesterol biosynthesis pathway highlighting the biologically active metabolites and pleotropic activities. Statins have wide-reaching immunomodulatory properties that are mainly driven by inhibition of the isoprenoids geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) to perform protein prenylation (ie, isoprenylation), which is a downstream effect of inhibiting hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the mevalonate pathway for the synthesis of cholesterol. Abbreviation: GPP, geranyl pyrophosphate.
effects that occur in cholesterol-dependent and -independent manners. Cholesterol is a major component of specialized membrane domains called lipid rafts, composed of sphingolipids and cholesterol in the exoplasmic leaflets and of phospholipids and cholesterol in their cytoplasmic leaflets [45]. These lipid raft domains play critical roles in various cellular signal transduction mechanisms. They can cluster to form large platforms where functionally related proteins interact to provide effective signal transduction, such as T-cell receptors and costimulatory molecules that form an immunological synapse to mediate cellular signaling [46]. Therefore, depletion of cholesterol in lipid raft domains can alter their structure and function, with a significant effect on cellular activation and signaling pathways [47]. In addition, statins reduce plasma levels of oxLDL cholesterol [48], thereby providing another mechanism by which the cholesterol-dependent effects of statins may attenuate CVD risk indirectly via reduction of inflammation and immune activation. In addition to these cholesterol-dependent mechanisms, statins also induce a number of pleotropic effects, such as antiinflammatory activities, independent of cholesterol, previously reviewed at length [48, 49]. Referring again to Figure 1, the
inhibition of the mevalonate pathway results in inhibition of synthesis of all metabolites in the mevalonate pathway, including dolichol and isoprenoids (20-carbon geranylgeranyl pyrophosphate [GGPP] and 15-carbon farnesyl pyrophosphate [FPP]) [42]. Thus, a perturbation in the synthesis of any of these metabolites may also be responsible for the pharmacological activity of statins. Geranylgeranyl-pyrophosphate and FPP bind to proteins, such as small GTPases (eg, Ras, Rho, and Rac), during their posttranslational modification to serve an important cellular mechanism for targeting of proteins to their site of activity in membranes. A number of observations support the role of isoprenylation in the pleotropic activities of statins. For example, inhibitors of isoprenyl transferase (the enzyme that transfers isoprenoids to proteins) reduce the expression of proinflammatory cytokines (eg, tumor necrosis factor α, interleukin 1β, and interleukin 6). Likewise, the antiinflammatory effects of statins can be reversed by FPP or GGPP but not by cholesterol or squalene. Therefore, inhibition of isoprenylation plays a major role in statin-mediated, cholesterol-independent pleotropic effects targeting the inflammatory and oxidative stress mechanisms in various inflammatory disease states. Statins affect several key functions of the immune system via reduction of isoprenylation through inhibition of HMG-CoA Statins and HIV
•
JID 2016:214 (Suppl 2)
•
S85
reductase, as discussed above, but also by means unrelated to inhibition of HMG-CoA reductase. There are some effects that may be of particular relevance to patients with HIV infection. For example, statins modulate T-cell activation and proliferation by inhibiting the interferon γ–inducible expression of major histocompatibility complex class II molecules and costimulatory molecules on endothelial cells and antigen-presenting cells, preventing antigen presentation to CD4+ T cells [48]. Similarly, in most studies, statins also cause a shift in the pattern of T-cell cytokine secretion, whereby there is a significant suppression of T-helper type 1 (Th1)–type cytokines with a concomitant increase in Th2-type cytokines. Finally, statins appear to significantly influence the circulating number and functional properties of T-regulatory cells (Tregs) [50]. One important aspect in the pathogenesis of CVD and other inflammatory conditions is the interaction between leukocytes and endothelial cells via a complex process involving the expression of cell-adhesion molecules. Statins interfere with the interaction between and expression of key adhesion molecules. Likewise, once leukocytes breach the vascular barrier, they are reliant on MMP expression for migration within the endothelial and smooth muscle cells. Statins appear to inhibit the secretion of MMPs, which could contribute to plaque stabilization. Last, oxidative stress also contributes to CVD development by contributing to endothelial dysfunction, vascular permeability, and induction of proinflammatory cytokines. Statins increase levels of nitric oxide synthase in endothelial cells to produce vascular nitric oxide, which has been shown to be beneficial in thwarting the effects of oxidative stress. IMPLICATIONS OF THE IMMUNOMODULATORY EFFECTS OF STATINS IN HIV-INFECTED INDIVIDUALS CVD Risk Reduction
In the general population, a number of landmark clinical trials have demonstrated that statins provide considerable benefit for both primary and secondary CVD risk reduction. The study perhaps most relevant to the HIV population comes from the JUPITER trial, in which subjects with a low LDL cholesterol level (2.0 mg/L) had a 44% relative risk reduction in major cardiovascular events during daily treatment with 20 mg of rosuvastatin [51]. These studies, which showed the tremendous benefits of statins, led to the current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines. These guidelines identify 4 types of patients who would benefit most from statin therapy: (1) those with high LDL levels (>190 mg/dL), (2) those with a history of known CVD, (3) those with diabetes, and (4) those aged 40–75 years with a Framingham risk score of >7.5% for a 10-year risk of CVD [52]. Because HIV infection is associated with enhanced inflammation, immune activation, and oxidative stress, the beneficial S86
•
JID 2016:214 (Suppl 2)
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Eckard et al
effects of statin therapy in HIV-infected patients cannot necessarily be extrapolated from the general population. Currently, there is a paucity of studies investigating the effect of statins on CVD events in HIV-infected individuals. The data are limited to observational studies or trials that have focused on surrogate markers of CVD. Completed and ongoing trials of statins with cardiovascular end points were recently reviewed [52]. One HIV-infected population in particular that may benefit differently from statin therapy to reduce CVD risk as compared to the general population are individuals who are otherwise considered low risk by traditional CVD risk calculators. Several studies have indicated that these risk calculators underestimate the risk for myocardial infarction and stroke, particularly those who are categorized as low risk (10-year Framingham risk score of
Cardiovascular Disease, Statins, and HIV Allison Ross Eckard,1 Eric G. Meissner,1 Inderjit Singh,1 and Grace A. McComsey2 1
Medical University of South Carolina, Charleston; and 2Case Western Reserve University, Cleveland, Ohio
Human immunodeficiency virus (HIV)–infected patients are at an increased risk of serious, non–AIDS-defining comorbidities, even in the setting of viral suppression with combination antiretroviral therapy. This increased risk is due in part to immune dysfunction and heightened inflammation and immune activation associated with chronic HIV infection. Statins have wide-reaching immunomodulatory effects, and their use in the HIV-infected population may be of particular benefit. In this article, we review the pathogenesis of increased inflammation during HIV infection and how it contributes to the risk of cardiovascular disease among HIV-infected individuals. We then we review the immunomodulatory effects of statins and how they may attenuate the risk of cardiovascular disease and other comorbidities in this unique patient population. Keywords. HIV; statins; hydroxy-3-methylglutaryl coenzyme A reductase inhibitors; cardiovascular disease; inflammation; immune activation.
Early, sustained viral suppression with combination antiretroviral therapy (cART) is now considered standard of care for human immunodeficiency virus (HIV) infection, as compelling data have shown that this approach reduces serious events, slows the progression of HIV disease, and decreases mortality [1, 2]. Even in the context of long-term viral suppression, however, HIV-infected individuals are still at an increased risk, compared with the general population, of developing serious non–AIDS-defining comorbidities, including cardiovascular disease (CVD), osteoporosis, neurocognitive impairment, and malignancies. Both direct and indirect effects of chronic HIV infection cause global immune dysfunction, including increased inflammation, immune activation, and immunosenescence, which contribute to the development of these comorbidities. Until the ultimate goal of HIV eradication is achieved, adjuvant therapies to cART aimed at further reducing inflammation is of paramount importance. Statins, hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, possess widereaching immunomodulatory effects, in addition to their potent lipid level–lowering properties, making them particularly attractive for study during HIV infection. In this review, we will first discuss the predominant mechanisms by which HIV may enhance inflammation and how this contributes to the pathogenesis of CVD and other comorbidities during HIV infection. Next, we review the immunomodulatory effects of statins and how they may attenuate the risk of CVD and other comorbidities in this unique patient population.
Correspondence: A. R. Eckard, Divisions of Infectious Diseases, Departments of Medicine and Pediatrics, Medical University of South Carolina, 135 Rutledge Ave, Charleston, SC 29425 ([email protected]). The Journal of Infectious Diseases® 2016;214(S2):S83–92 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/infdis/jiw288
INFLAMMATION IN COMBINATION ANTIRETROVIRAL–TREATED HIV INFECTION
Given the ongoing viral replication and CD4+ T-cell depletion in untreated HIV infection, the presence of increased inflammation is perhaps expected. Arguably, however, a sustained increase despite viral suppression with cART is perhaps less mechanistically apparent. Identification of factors driving inflammation during combination antiretroviral–treated chronic HIV infection is imperative when considering available and novel therapeutic approaches for outcome modulation. Here, we briefly review several factors potentially subject to modulation by statin therapy; these and other factors are covered in greater depth in additional articles within this supplement. Host-Virus Interaction
While modern cART efficiently suppresses HIV replication below the limit of detection in blood, promotes CD4+ T-cell recovery and stability, and decreases levels of inflammatory and immune activation markers [3, 4], current evidence suggests that viral replication persists, likely within lymphoid organs, through cell-to-cell transmission, and/or through homeostatic proliferation [5–7]. Importantly, many markers of inflammation and immune activation are relatively nonspecific, and the precise events driving their production can be challenging to ascertain. However, this subdetectable viral replication likely contributes in part to the increased inflammation in treated HIV infection. Likewise, the residual impact of CD4+ T-cell depletion during acute and untreated HIV infection can persist, despite subsequent cART-induced viral suppression. For example, a significant depletion of gut-associated lymphoid tissue occurs during acute infection, which never fully recovers even with prolonged treatment [8–10]. This permanent alteration of gut immunity and integrity allows an increase in microbial translocation. The microbes themselves and their products (eg, lipopolysaccharide, Statins and HIV
•
JID 2016:214 (Suppl 2)
•
S83
a component of the cell wall of gram-negative bacteria) circulate in the plasma, bind to and upregulate various receptors, and are associated with markers of immune activation [11–14]. In fact, plasma gut epithelial barrier integrity markers independently predict mortality, even after adjustment for CD4+ T-cell count, in individuals with treated HIV infection and a history of AIDS [13]. Finally, in some patients, deemed immune nonresponders, the CD4+ T-cell count does not rise to near-normal levels despite prolonged viral suppression [15, 16]. These patients have higher levels of inflammation and immune activation markers, with presumably comparable degrees of subdetectable viral persistence, implicating a permanent residual impact of host immunity that may be due to thymic fibrosis, lymphoid organ fibrosis, irreversible loss of mucosal immunity, T-cell exhaustion, or other mechanisms [17–23]. Antiretroviral Drug Effects
While modern cART regimens exhibit improved safety, improved tolerability, and a reduction in side effects relative to their predecessors, cART medications themselves may still have an impact on inflammation. An example is the use of protease inhibitors (PIs), which may contribute both directly and indirectly to immune dysfunction and inflammation during HIV infection. PIs have been associated with dyslipidemia and metabolic derangements that then contribute in a complicated interplay to affect inflammation and immune activation, as discussed in greater depth by Koethe et al elsewhere in this supplement [24]. PIs have also been shown to trigger premature senescence in endothelial cells and circulating peripheral blood mononuclear cells (PBMCs) of PI-treated HIV-infected patients [25]. However, it should be noted that newer PIs have not demonstrated a clear association with inflammation when compared to other non-PI therapies [26]. Similarly, integrase inhibitors show a broadly neutral effect on lipids, and there is some evidence to suggest that they may cause a modest decline in inflammation and immune activation [26, 27]. Comorbid Conditions
Increased inflammation in combination antiretroviral–treated patients with HIV infection may also be related to comorbid conditions, which tend to occur frequently in HIV-infected individuals. The high incidences of smoking, diabetes, dyslipidemia, and increased visceral adiposity may contribute to inflammation and immune activation independent of and/or as a result of HIV infection [28, 29]. A clear example that was recently described is the effect of oxidized low-density lipoprotein (oxLDL) cholesterol on monocyte activation. oxLDL cholesterol is a proinflammatory form of LDL cholesterol that is often found within atheromatous plaques and contributes to the generation of foam cells, an integral step in instigating an acute coronary event (see below). Zidar et al showed that HIV-infected patients have both increased plasma levels of S84
•
JID 2016:214 (Suppl 2)
•
Eckard et al
oxLDL, as well as increased monocyte expression of oxLDL receptors [30]. Plasma oxLDL levels were also correlated with markers of monocyte activation, suggesting that increased oxLDL levels serve as a driver of monocyte immune activation during HIV infection [30]. INFLAMMATION IN THE PATHOGENESIS OF CVD AND OTHER COMORBIDITIES IN HIV-INFECTED INDIVIDUALS
Early epidemiologic studies suggested that antiretroviral drugs, especially PIs, were the primary cause of the increased risk of myocardial infarction seen in the HIV-infected population [31], owing to their well-recognized lipid and metabolic complications, which directly contribute to CVD risk. However, subsequent studies have demonstrated that HIV infection itself is independently associated with an increased risk of CVD [32–34], and despite effective viral suppression with cART, atherosclerotic CVD events, such as myocardial infarction and ischemic stroke, still occur more commonly in HIV-infected patients as compared to the general population [35, 36]. The vast amount of evidence that supports the fact that inflammation and immune activation are strongly linked to the development of CVD in the general population and in HIVinfected individuals is beyond the scope of this review but was reviewed extensively in a previous supplement of The Journal of Infectious Diseases [37, 38]. Briefly, inflammation is thought to be critical in the development of CVD at all stages [39], and equally important, both innate and adaptive immunity play integral roles. Moreover, the endothelium is a biologically active organ that becomes activated in response to injury and inflammatory mediators (including elevated circulating levels of oxLDL cholesterol [40]), causing upregulation of cellular adhesion molecules, expression of inflammatory cytokines, monocyte recruitment into the intimal space, and differentiation of monocytes into macrophages that engulf oxLDL cholesterol, producing foam cells that aggregate to form a fatty streak covered by a fibrous cap. Signaling between macrophages and T cells can promote release of matrix-degrading enzymes known as matrix metalloproteinases (MMPs), which destroy collagen within the fibrous cap, making it unstable and prone to rupture. This leads to an acute coronary event [41]. IMMUNOMODULATORY PROPERTIES OF STATINS
Statins are a class of prescription drugs that inhibit the rate-limiting enzyme, HMG-CoA reductase, in the mevalonate pathway for the synthesis of cholesterol (Figure 1). They bind to HMGCoA reductase at nanomolar concentrations as competitive inhibitors and replace the natural substrate, HMG-CoA [42]. Statins are well known for their cholesterol level–lowering effects in both plasma and cell membranes and, accordingly, their use as primary and secondary CVD prevention [43, 44]. However, statins also have wide-reaching immunomodulatory
Figure 1. Cholesterol biosynthesis pathway highlighting the biologically active metabolites and pleotropic activities. Statins have wide-reaching immunomodulatory properties that are mainly driven by inhibition of the isoprenoids geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) to perform protein prenylation (ie, isoprenylation), which is a downstream effect of inhibiting hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the mevalonate pathway for the synthesis of cholesterol. Abbreviation: GPP, geranyl pyrophosphate.
effects that occur in cholesterol-dependent and -independent manners. Cholesterol is a major component of specialized membrane domains called lipid rafts, composed of sphingolipids and cholesterol in the exoplasmic leaflets and of phospholipids and cholesterol in their cytoplasmic leaflets [45]. These lipid raft domains play critical roles in various cellular signal transduction mechanisms. They can cluster to form large platforms where functionally related proteins interact to provide effective signal transduction, such as T-cell receptors and costimulatory molecules that form an immunological synapse to mediate cellular signaling [46]. Therefore, depletion of cholesterol in lipid raft domains can alter their structure and function, with a significant effect on cellular activation and signaling pathways [47]. In addition, statins reduce plasma levels of oxLDL cholesterol [48], thereby providing another mechanism by which the cholesterol-dependent effects of statins may attenuate CVD risk indirectly via reduction of inflammation and immune activation. In addition to these cholesterol-dependent mechanisms, statins also induce a number of pleotropic effects, such as antiinflammatory activities, independent of cholesterol, previously reviewed at length [48, 49]. Referring again to Figure 1, the
inhibition of the mevalonate pathway results in inhibition of synthesis of all metabolites in the mevalonate pathway, including dolichol and isoprenoids (20-carbon geranylgeranyl pyrophosphate [GGPP] and 15-carbon farnesyl pyrophosphate [FPP]) [42]. Thus, a perturbation in the synthesis of any of these metabolites may also be responsible for the pharmacological activity of statins. Geranylgeranyl-pyrophosphate and FPP bind to proteins, such as small GTPases (eg, Ras, Rho, and Rac), during their posttranslational modification to serve an important cellular mechanism for targeting of proteins to their site of activity in membranes. A number of observations support the role of isoprenylation in the pleotropic activities of statins. For example, inhibitors of isoprenyl transferase (the enzyme that transfers isoprenoids to proteins) reduce the expression of proinflammatory cytokines (eg, tumor necrosis factor α, interleukin 1β, and interleukin 6). Likewise, the antiinflammatory effects of statins can be reversed by FPP or GGPP but not by cholesterol or squalene. Therefore, inhibition of isoprenylation plays a major role in statin-mediated, cholesterol-independent pleotropic effects targeting the inflammatory and oxidative stress mechanisms in various inflammatory disease states. Statins affect several key functions of the immune system via reduction of isoprenylation through inhibition of HMG-CoA Statins and HIV
•
JID 2016:214 (Suppl 2)
•
S85
reductase, as discussed above, but also by means unrelated to inhibition of HMG-CoA reductase. There are some effects that may be of particular relevance to patients with HIV infection. For example, statins modulate T-cell activation and proliferation by inhibiting the interferon γ–inducible expression of major histocompatibility complex class II molecules and costimulatory molecules on endothelial cells and antigen-presenting cells, preventing antigen presentation to CD4+ T cells [48]. Similarly, in most studies, statins also cause a shift in the pattern of T-cell cytokine secretion, whereby there is a significant suppression of T-helper type 1 (Th1)–type cytokines with a concomitant increase in Th2-type cytokines. Finally, statins appear to significantly influence the circulating number and functional properties of T-regulatory cells (Tregs) [50]. One important aspect in the pathogenesis of CVD and other inflammatory conditions is the interaction between leukocytes and endothelial cells via a complex process involving the expression of cell-adhesion molecules. Statins interfere with the interaction between and expression of key adhesion molecules. Likewise, once leukocytes breach the vascular barrier, they are reliant on MMP expression for migration within the endothelial and smooth muscle cells. Statins appear to inhibit the secretion of MMPs, which could contribute to plaque stabilization. Last, oxidative stress also contributes to CVD development by contributing to endothelial dysfunction, vascular permeability, and induction of proinflammatory cytokines. Statins increase levels of nitric oxide synthase in endothelial cells to produce vascular nitric oxide, which has been shown to be beneficial in thwarting the effects of oxidative stress. IMPLICATIONS OF THE IMMUNOMODULATORY EFFECTS OF STATINS IN HIV-INFECTED INDIVIDUALS CVD Risk Reduction
In the general population, a number of landmark clinical trials have demonstrated that statins provide considerable benefit for both primary and secondary CVD risk reduction. The study perhaps most relevant to the HIV population comes from the JUPITER trial, in which subjects with a low LDL cholesterol level (2.0 mg/L) had a 44% relative risk reduction in major cardiovascular events during daily treatment with 20 mg of rosuvastatin [51]. These studies, which showed the tremendous benefits of statins, led to the current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines. These guidelines identify 4 types of patients who would benefit most from statin therapy: (1) those with high LDL levels (>190 mg/dL), (2) those with a history of known CVD, (3) those with diabetes, and (4) those aged 40–75 years with a Framingham risk score of >7.5% for a 10-year risk of CVD [52]. Because HIV infection is associated with enhanced inflammation, immune activation, and oxidative stress, the beneficial S86
•
JID 2016:214 (Suppl 2)
•
Eckard et al
effects of statin therapy in HIV-infected patients cannot necessarily be extrapolated from the general population. Currently, there is a paucity of studies investigating the effect of statins on CVD events in HIV-infected individuals. The data are limited to observational studies or trials that have focused on surrogate markers of CVD. Completed and ongoing trials of statins with cardiovascular end points were recently reviewed [52]. One HIV-infected population in particular that may benefit differently from statin therapy to reduce CVD risk as compared to the general population are individuals who are otherwise considered low risk by traditional CVD risk calculators. Several studies have indicated that these risk calculators underestimate the risk for myocardial infarction and stroke, particularly those who are categorized as low risk (10-year Framingham risk score of
