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Is increased development of cardiovascular disease in HIV positive patients due to persistent immune activation?

Introduction

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Human immunodeficiency virus (HIV) infection has shifted to a more medically controllable chronic disease, with non-acquired immunodeficiency syndrome (AIDs) related diseases, such as cardiovascular disease, being the main cause of morbidity and mortality (Vachiat et al., 2017). There is increased prevalence of traditional risk factors, smoking for example, in HIV-infected individuals. Additionally, the effects of certain antiretroviral regimens lead to dyslipidemia, insulin resistance, and endothelial dysfunction. However, the role of persistent immune activation and inflammation is central to the increased risk of CVD (Vachiat et al., 2017).

The development of CVD a complex process involving endothelial dysfunction and arterial inflammation. Persistent immune activation most likely exacerbates atherogenesis. With increased use of combination antiretroviral therapy (cART), CVD has become one of the leading causes of morbidity and mortality in HIV-positive individuals. Several epidemiologic studies in HIV-infected patients have shown an increased risk of cardiovascular complications that persists despite controlling traditional CVD risk factors. This is suggestive of contributory effects of nontraditional risk factors such as immune activation (Nou, Lo and Grinspoon, 2016).

Human immunodeficiency virus and cardiovascular disease

Human Immunodeficiency Disease (HIV) and cardiovascular disease (CVD) are two of the leading causes of morbidity and mortality, worldwide. Cardiovascular disease, being the number one cause of mortality worldwide, claimed the lives of 17.3 million individuals in 2008 alone. Discovered in 1981, HIV, considered to be the worlds leading infectious killer has claimed more than 25 million lives over the past three decades. Despite improved sexual education, preventative measures and treatment, the HIV epidemic continues to spread (Krikke et al., 2014).

Over the last two decades, the prognosis for HIV-positive individuals has tremendously improved due to administration of combination antiretroviral therapy (cART) thereby increasing the life expectancy of HIV-positive individuals (Martin-Iguacel, Llibre and Friis-Moller, 2015). However, owing to their longer lifespan, HIV has become a chronic disease with non-acquired immunodeficiency syndrome (AIDS) defining illnesses being the main cause of morbidity and mortality amongst HIV-positive patients as opposed to severed opportunistic complications associated with advanced immunodeficiency (Vachiat et al., 2017; (Martin-Iguacel, Llibre and Friis-Moller, 2015).

Cardiovascular disease is one of the most frequent causes of mortality amongst HIV-positive patients. Studies performed in the United States and Europe suggest that HIV infection increased the overall risk of CVD development by 1.5 to 2.0-fold when compared to their seronegative counterparts. Individuals with HIV also present with a 4.5-fold increased rate of cardiomyopathy, heart failure, hypertension, arrhythmia and dyslipidaemia (Vachiat et al., 2017).

The underlying mechanism resulting in the increased risk of non-AIDS complications most likely is multifactorial, including comorbidities and ARV-related toxicities. Two key factors that have strongly been linked to the development of cardiovascular disease, in HIV-positive patients, is persistent immune activation and inflammation that persists despite effective ARV treatment. (Hsue, Deeks and Hunt, 2012; Longenecker, Sullivan and Baker, 2016). The development of atherosclerosis, one of the most prominent forms of cardiovascular disease, involves endothelial dysfunction and arterial inflammation. Systemic inflammation exacerbates atherogenesis and chronic HIV comprises of persistent immune activation and inflammation (Nou, Lo and Grinspoon, 2016).

Immune activation, inflammation and cardiovascular disease

Human immunodeficiency virus (HIV) infection activates the innate and adaptive immune systems which enables a lifelong viral latent and chronic infection. This forms the basis of ongoing immune activation and progressive immunodeficiency; characterized by increased cell turnover, apoptosis and activation-induced death of cells of the immune system (Deeks et al, 2012). Immune activation refers to an altered immune state with HIV infection which results in increased T cell turnover with increased levels of activated T and B cells, accompanied by elevated inflammatory cytokines and chemokines. There are various factors that contribute to persistent immune activation; chronic viral replication, viral proteins, microbial translocation and CD4+ T cell depletion (Appay et al, 2008; Krikke et al, 2014). Systemic inflammation has been linked to CVD in HIV-positive patients and although ARV treatment reduces immune activation, inflammatory markers remain increased as opposed to uninfected individuals (Pereyra et al., 2012).

Persistent immune activation, inflammation and immune dysfunction occurs despite maintained viral suppression. T cell activation, microbial translocation, monocyte/macrophage-related inflammation, dysfunctional immunoregulatory responses, inflammatory cytokines, endothelial activation and hypercoagulation; all of which are associated with HIV infection, contribute to the increased risk of CVD (Martin-Iguacel, Llibre and Friis-Moller, 2015; (Pereyra et al., 2012). Cardiovascular disease risk may also be implicated by inflammation through the proatherogenic effects it has on lipid metabolism (Martin-Iguacel, Llibre and Friis-Moller, 2015). The chronic phase of HIV disease poses a high risk of endothelial dysfunction and subclinical atherosclerosis. Endothelial dysfunction, characterized by elevated levels of endothelial adhesion molecules, may result consequently from the release of cytokines by activated monocytes or directly by HIV viral proteins that alter signaling pathways (Sokoya et al., 2017).

Persistent immune activation

Mechanisms by which HIV and the hosts immune system may induce immune activation is multi-factorial, each of which synergistically contribute consequentially to persistent immune activation and immune dysfunction (Paiardini and Müller-Trutwin, 2013; Pereyra et al., 2012).
HIV replication and immune response to the virus
During HIV infection, the direct innate and adaptive immune response against the virus and viral antigens initiates immune activation (Paiardini and Müller-Trutwin, 2013). The human immunodeficiency virus activates and induces strong T cell responses, particularly CD8+ T cells, which persists due to the continuous replication of the virus (Appay and Sauce, 2008). Immune activation and inflammation correlate with the extent of viraemia in the patient, supporting the contribution of HIV replication to immune activation (Paiardini and Müller-Trutwin, 2013). Despite the efficacy of antiretroviral (ARV) treatment, low levels of residual viraemia may result in ongoing replication. Active replication contributes to persistent immune activation and inflammation. While the direct contribution of HIV replication to chronic immune activation is recognized, evidence indicate that even at high replicative cycles, ongoing replication is insufficient to induce pathological levels of immune action (Paiardini and Müller-Trutwin, 2013; Nou, Lo and Grinspoon, 2016).
Viral proteins and immune activation
Gene products may directly induce activation of lymphocytes and macrophages, resulting in the production of pro-inflammatory cytokines and chemokines. The envelope protein gp120 can activate cells and enhance their responsiveness to activation through binding to CD4 or co-receptors. Accessory protein, Nef, may lead to lymphocyte activation either directly or through the infection of macrophages (Appay and Sauce, 2008). Nef has also been shown to decrease endothelial nitric oxide production, induce endothelial apoptosis and increase pro-inflammatory cytokine release from macrophages (Nou, Lo and Grinspoon, 2016). Furthemore, certain HIV proteins can enhance and activate TNF-receptor signaling which leads to persistent viral replication in infected cells through the activation of nuclear factor kappa beta (NF??) and apoptosis of uninfected T-cells (Sokoya et al., 2017).
Co-infections
The immunodeficient state induced by HIV contributes to the chronic immune activation through increased susceptibility to opportunistic infections. Through stimulation of the immune cells, opportunistic pathogens may play a central role in sustaining persistent activation of the immune system in HIV-infection (Paiardini and Müller-Trutwin, 2013; (Sokoya et al., 2017).

Loss of mucosal integrity of the gastrointestinal tract and microbial translocation
A key contributor to persistent immune activation is the loss of integrity and therefore immune function of the gastrointestinal (GI) tract. CD4+ T cells, particularly those expressing CCR5, are severely depleted from the GI tract in the first few weeks of infection. The massive loss of mucosal CD4+ T cells is associated with a loss of intestinal epithelial cells, disruption of tight junctions and consequentially; compromised integrity of the GI tract mucosal intestinal barrier (Paiardini and Müller-Trutwin, 2013). The barrier prevents translocation of the normal flora in the intestinal tract, restricting the pathogens to the lamina propia and mesenteric lymph nodes. When the integrity thereof is compromised, microbial translocation ensues from the gut to the systemic immune system, resulting in immune activation. (Appay and Sauce, 2008; Nou, Lo and Grinspoon, 2016). The microbial products stimulate several toll-like receptors (TLRs) and stimulate the production of pro-inflammatory cytokines such as TNF-?, IL-6, IL-1? and type I interferons. While essential in the setting of acute infection, these responses may contribute to persistent immune activation in chronic HIV infection. Overproduction of TNF, by inducing enterocyte apoptosis, can be harmful for the integrity of the epithelial barrier of the GI tract further exacerbating the process of microbial translocation and immune activation. (Paiardini and Müller-Trutwin, 2013; Sokoya et al., 2017). In a clear majority of studies in chronic HIV infection, an association between HIV infection and increased lipopolysaccharide (LPS) levels, an indicator of microbial translocation, have been described where LPS is directly correlated to measures of immune activation (Paiardini and Müller-Trutwin, 2013; Appay and Sauce, 2008). Lipopolysaccharide, apart from being able to mount an immune response, can increase the tissue factor on monocytes which in turn may result in a procoagulant effect and increase the risk of thrombosis. The microbial product has also been shown to have harmful effects on endothelial function, causing rapid and profound impairment of endothelial-dependent relaxation; further implicating the risk for potential CVD development (Hsue, Deeks and Hunt, 2012).
Monocyte activation
Monocytes, the precursors of macrophages, are present in atherosclerotic lesions and produce inflammatory cytokines. Lipopolysaccharide was shown to activate monocytes, leading to the production of tissue factor, potentially accelerating the formation of an acute thrombus. While monocytes are likely to play a key role in HIV-associated CVD, the extent to which monocyte activation causes cardiovascular disease in HIV infection, independently of other inflammatory pathways, remains to be investigated (Hsue, Deeks and Hunt, 2012).
Persistent immune activation causes a significant cellular turnover, senescence and apoptosis. The detrimental consequences of systemic immune activation are multifactorial. While some may be particular to HIV, such as immune system dysregulation, many of the morbidities are similar to those occurring during ageing that affect various organ systems such as cardiovascular disease.

How does persistent immune activation in HIV-positive patients cause cardiovascular disease
The hallmark of CVD is the process of atherosclerosis and atherothrombosis. The development of atherosclerosis involves endothelial dysfunction and arterial inflammation. Systemic inflammation exacerbates atherogenesis. Several studies show a relationship between cardiovascular disease and chronic inflammatory disorders. Chronic HIV is also considered a state of persistent inflammation. As a result of persistent immune activation; activated T cells and monocytes sustain systemic inflammation, hypercoagulation and endothelial dysfunction (Vachiat et al., 2017; Hsue, Deeks and Hunt, 2012). Even patients on ARV treatment with complete viral suppression still have the residual risk for CVD because of the persistent immune activation and inflammation (Vachiat et al., 2017).
Both innate and adaptive immunity play a role in the pathogenesis of CVD in HIV-positive individuals. Oxidized low-density lipoprotein are recognized as pathogens by dendritic cells, part of the innate immune system. The dendritic cells present these antigens to naive T cells, leading to T-cell activation. Activated T cells are significantly increased in HIV-infected individuals and correlate with viral load, subsequently disease stage. Some studies have shown that T cell and monocyte activation are independently associated with subclinical atherosclerosis in HIV-infected individuals on ARV treatment (Sinha et al., 2016).
Atherosclerosis is a chronic inflammatory condition in which immune and nonimmune mechanisms induce endothelial dysfunction, the first step in atherogenesis. In turn, endothelial dysfunction induces the expression of pro-thrombotic and pro-inflammatory cytokine adhesion molecules that further propagate the inflammatory response, attracting monocytes T-cells. Once in the intima, macrophages phagocytize oxidized low-density lipoproteins (ox-LDL), leading to foam cell formation and eventually formation of plaques, the hallmark of atherosclerosis.
Given the central role of monocyte-derived macrophages in atherogenesis, it is not surprising that several lines of evidence suggest a relationship between macrophage activation and CVD in HIV. In addition to activation, HIV infection may also lead to macrophage dysfunction in cholesterol handling, which could contribute to the development of atherosclerosis. Cholesterol can be moved from macrophages to high-density lipoprotein in a process known as reverse cholesterol transport, which is thought to protect against atherosclerosis. In contrast to monocytes/macrophages, a relationship between T-cell activation and CVD in patients with HIV is less certain. In cross sectional studies, the percentage of activated T-cells (based on CD38 and HLA-DR expression) was associated with prevalence of CIMT and carotid artery stiffness.
Endothelial dysfunction of cardiovascular disease in human immunodeficiency viral infections
Viral replication is strongly associated with vascular dysfunction (Hsue, Deeks and Hunt, 2012). Endothelial dysfunction, associated with CVD, has been described in many HIV-positive patients. There is an intricate interplay between endothelial function and inflammation. Markers of endothelial activation, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) both of which are up-regulated by inflammatory cytokines, are elevated in patients early after HIV infection (Vachiat et al., 2017). A study performed by Sinha et al (2012) suggested that T-cell activation plays a role in endothelial dysfunction at a microvascular level in HIV-infected individuals and that poor macrovascular function in HIV infection might be secondary to diseased microvasculature, leading to CVD (Sinha et al., 2016).
Activation of the overlying endothelium is a critical first step in atherosclerosis. In response to proatherogenic stimuli, the endothelium alters production of nitric oxide (NO), which affects vascular tone increases permeability, allowing entry of lipids and the expression of chemokines like monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules like vascular cell adhesion molecule-1 (VCAM-1). This results in leukocyte transendothelial migration. These effects are observed as a thickening of the tunica intima associated with the presence of sub-endothelial pools and leukocytes in the vessel wall (Nou, Lo and Grinspoon, 2016). Once in the arterial wall macrophages recognize modified forms of low-density lipoprotein (LDL) such as oxidized LDL (ox-LDL) resulting in their differentiation into foam cells. Foam cells are characterized by intracellular accumulation of lipids and production of pro-inflammatory cytokines and matrix metalloproteinases (MMP) (Nou, Lo and Grinspoon, 2016). Fragments of LDL are also presented to naive T-cells that can later enter the vessel wall and secrete pro- inflammatory molecules which leads to changes in macrophages, endothelial cells, and smooth muscle cells. This further promotes further progression of the atherosclerotic plaque. The area of intimal thickening may progress into a fibroatheroma characterized by the presence of a necrotic (or lipid) core. The necrotic core is largely defined by two features. The first involves the presence of dead or dying cells, largely macrophages, releasing intracellular lipids into the lipid core. The second features a dearth of extracellular matrix proteins, likely because of MMPs and other peptidases that contribute to structural instability of the arterial wall (Nou, Lo and Grinspoon, 2016).

Other notable components of fibroatheromas are intra-plaque calcifications and the overlying fibrous cap. The fibrous cap lends structural support to the growing plaque, but unfortunately, some fibrous caps are vulnerable to erosion or rupture, resulting in thrombus formation and potentially myocardial infarction, stroke, or sudden cardiac death.
An increase in immune activation and systemic inflammation results in the release of inflammatory, coagulation and endothelial mediators at the level of the vascular wall. Atherogenesis is enhanced by adhesion and migration of activated T cells to the vascular wall resulting in advanced and unstable atherosclerotic plaques, a process which is aggravated in HIV infection. An important step to decrease the CVD burden in HIV-infected patients should be directed towards decreasing immune activation and the subsequent inflammation.

Intervention
Given the evidence linking inflammation to cardiovascular disease in HIV infection, specific anti-inflammatory therapies beyond antiretroviral treatment are required. Since there are several parallel immune activation pathways synergistically interacting with each other to potentially mediate the risk for CVD in HIV infection; a key step toward an effective intervention is to identify specific risk factors and potential immunologic targets (Hsue, Deeks and Hunt, 2012). Primary and secondary prevention of CVD in the HIV population is importance. Currently, it is based on guideline recommendations from the general population, which may not be fully fitting for HIV-positive persons (Martin-Iguacel, Llibre and Friis-Moller, 2015). Early ARV treatment initiation may be helpful in decreasing the risk of CVD. The treatment of patients at risk of CVD should include drugs with improved lipid and metabolic profiles and limited potential of drug– drug interactions with co-medications (Martin-Iguacel, Llibre and Friis-Moller, 2015). Early ARV treatment may preserve the integrity of the GI tract and reduce microbial translocation. Other benefits include maintenance of HIV-specific CD4+ T-cells, decrease of the turnover rate and activation of CD4+ and CD8+ T-cells and inhibition of viral progression (Sokoya et al., 2017).
Various therapeutic measures have been explored with the aim of reducing systemic immune activation in HIV-infected individuals (Sokoya et al., 2017).
Given the pleiotropic effects thereof statins may reduce cardiovascular events among HIV-infected patients. Besides their ability to lower LDL cholesterol level, statins decrease monocyte activation, chemoattraction as well as vascular inflammation and decrease noncalcified plaque volume in HIV-infected patients (Grinspoon, 2014; Nou, Lo and Grinspoon, 2016).
Conclusion
Due to the availability and administration of effective ARV treatment, the incidence of HIV/AIDS-related deaths have decreased significantly. However, owing to a longer lifespan, cardiovascular disease has become a significant cause of morbidity and mortality amongst HIV-positive individuals. Multiple factors play a role in the development of CVD in HIV-positive patients; including traditional risk factors, ARV treatment related toxicities and persistent immune activation associated immune dysregulation. The assessment of prognostic markers of the immunological pathways implicated in the pathogenesis of immune mediated cardiovascular disease will aid in the identification of targets for novel therapeutic interventions.

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