The Role of Platelet-Activating Factor in Chronic Inflammation, Immune Activation, and Comorbidities Associated with HIV Infection

Abstract

With the advent of highly effective antiretroviral therapy, cardiovascular disease has become an important cause of morbidity and mortality among people with treated HIV-1, but the pathogenesis is unclear. Platelet-activating factor is a potent lipid mediator of inflammation that has immunomodulatory effects and a pivotal role in the pathogenesis of inflammatory disorders and cardiovascular disease. Limited scientific evidence suggests that the platelet-activating factor pathway may be a mechanistic link between HIV-1 infection, systemic inflammation, and immune activation that contribute to pathogenesis of chronic HIV-related comorbidities, including cardiovascular disease and HIV-associated neurocognitive disorders. In this review, we examine the mechanisms by which the cross-talk between HIV-1, immune dysregulation, inflammation, and perturbations in the platelet-activating factor pathway may directly affect HIV-1 immunopathogenesis. Understanding the role of platelet-activating factor in HIV-1 infection may pave the way for further studies to explore therapeutic interventions, such as diet, that can modify platelet-activating factor activity and use of platelet-activating factor inhibitors that might improve the prognosis of HIV-1 infected patients.

Figure 1

Platelet-activation factor and its catabolic enzyme have a major role in atherogenesis. The reported atherogenic activities of oxidized low-density lipoprotein can be attributed to platelet-activation factor and platelet-activation factor-like lipids. Platelet-activation factor produced during low-density lipoprotein oxidation leads to endothelial dysfunction and in parallel it induces the release of reactive oxygen species, which leads to further low-density lipoprotein oxidation. Macrophages take up oxidized low-density lipoprotein through scavenger receptors (such as CD36) and form foam cells. The increased platelet-activation factor activity works vice versa as it activates endothelial cells and blood cells to further produce platelet-activation factor and promote atherogenesis. The catabolic enzyme of platelet-activation factor, lipoprotein-associated phospholipase A₂, has dual role in inflammation and oxidative stress and complex effects on atherogenesis. PAF: platelet-activation factor; LDL: low-density lipoprotein; OxLDL: oxidized low-density lipoprotein; ROS: reactive oxygen species; Lp-PLA₂: lipoprotein-associated phospholipase A₂.

Figure 2

Anti-inflammatory effects of platelet-activation factor-like lipids included oxidized phospholipids. In the setting of acute inflammation where lipopolysaccharides and lipoteichoic acid expressed on pathogens have major pro-inflammatory effects, anti-inflammatory effects of platelet-activation factor-like lipids on innate immunity are more prominent. The oxidized phospholipids and platelet-activation factor-like lipids (either present in pathogens or in host cells) may have complex effects on endothelial barrier (1). Oxidized phospholipids also inhibit oxidative burst in neutrophil granulocytes (2) and action of bacterial endotoxin and nuclear factor-kB activation in monocytes/macrophages via a multi-hit mechanism (3). Oxidized phospholipids were also shown to disrupt lipid rafts, thus preventing formation of signaling complex of toll-like receptor 4 with intracellular adaptors within caveolin-rich membrane domains. In addition, oxidized phospholipids can reduce adaptive immune responses through several mechanisms: a) inhibition of production of proinflammatory cytokines such as interleukin-12 and tumor necrosis factor-α by antigen presenting cells (monocytes/macrophages, dendritic cells) (4); b) inhibition of maturation of dendritic cells induced by lipopolysaccharides and CD40L (5); c) induction of anergy in T-cells and reduced proliferation (6); d) inhibition of T-cell activation and function such as production of pro-inflammatory cytokines (interferon-γ and interleukin-2), cytotoxicity of CD8⁺ T-cells, and the expression of de novo synthesized activation markers (CD25) (7). PAF: platelet-activation factor; EC: endothelial cell; MNC: mononuclear neutrophil cell; LPS: lipopolysaccharide; LBP: lipopolysaccharide binding protein; IL: interleukin; TNF: tumor necrosis factor; DC: dendritic cell; TLR: toll-like receptor; NF-κB: nuclear factor kappa B.

Figure 3

Pro-inflammatory effects of platelet-activation factor-like lipids included oxidized phospholipids. In the setting of chronic inflammation, pro-inflammatory effects of oxidized phospholipids and platelet-activation factor-like lipids are more prominent. Oxidized phospholipids and platelet-activation factor-like lipids can (1) cause endothelial cell barrier dysfunction through multiple mechanisms including reduced expression gap junctions and tight junctions, (2) stimulate production of chemokines, (3) directly promote adhesion of polymorphonuclear neutrophils and monocytes to endothelial cells, (4) upregulate cell adhesions molecules (such as β1-integrins, lymphocyte function-associated antigen-1, P-selectin). (5) Under specific conditions or in certain cell types, oxidized phospholipids may be agonistic for toll-like receptor 4 (e.g. through binding to unknown alternative co-receptors other than CD14, (6) increase production of pro-inflammatory cytokines such as interleukins-1β, -6, and -8 and tumor necrosis factor-α in tissue monocyte-derived macrophages, (7) induce surface expression of CD86 and major histocompatibility complex class II in immature dendritic cells, (8) reduce production of anti-inflammatory cytokines such as IL-10 from T-cells, interfere with the process of T-cell activation and upregulate formation of Th17, which have been implicated in a number of inflammatory and autoimmune diseases. PAF: platelet-activation factor; EC: endothelial cell; PMNC: polymorphonuclear neutrophil cell; MNC: mononuclear neutrophil cell; IL: interleukin; TNF: tumor necrosis factor; DC: dendritic cell; TLR: toll-like receptor; NF-κB: nuclear factor kappa B; MHC: major histocompatibility complex.

Figure 4

The crosstalk between platelet-activating factor, HIV-1, inflammation, immunity, and chronic comorbidities. Overall, in chronic HIV-1 infection there is a vicious cycle of increased systemic inflammation, coagulation, immune activation, increased production of oxidized lipids and platelet-activating factor that may directly affect cells and tissues and lead to end-organ disease (1). Platelet-activating factor may exert both pro-inflammatory and anti-inflammatory effects, depending on the biologic context (Fig. 2, 3). In chronic HIV-1 infection, the pro-inflammatory effects are more prominent since there is chronic activation of the platelet-activating factor pathway that may result in increased lysophosphatidylcholine formation (2). It is known to increase coagulation and systemic inflammation, affect the pathogenesis of many comorbidities including atherogenesis (Fig. 1), and cause immunomodulation (Fig. 2, 3; Table 2) (1). In addition, there is a dynamic cross-talk between HIV-1 and platelet-activating factor since HIV-1 affects the platelet-activating factor pathway and vice versa (3). Anti-retroviral therapy may also directly affect the platelet-activating factor pathway. Platelet-activating factor has direct effects on vascular permeability, atherogenesis (Fig. 1, Table 2) as well as the overall angiogenesis (4). Platelet-activating factor is a neurotoxin that also mediates HIV-infected macrophage-astroglia interactions and HIV-associated neurocognitive disorder pathogenesis (5). Platelet-activating factor can also cause immunomodulation and affect immune activation through direct effects on granulocytes, monocytes/macrophages, lymphocytes, and dendritic cells (6). The above interactions are not limited to discrete pathways, but are part of interrelated multiple feedback loops. PAF: platelet-activating factor; ART: antiretroviral therapy; CVD: cardiovascular disease; HAND: HIV-associated neurocognitive disorder.