Oxidized LDL Levels Are Increased in HIV Infection and May Drive Monocyte Activation

Zidar, David A.; Juchnowski, Steven; Ferrari, Brian; Clagett, Brian; Pilch-Cooper, Heather A.; Rose, Shawn; Rodríguez, Benigno; McComsey, Grace A.; Sieg, Scott F.; Mehta, Nehal N.; Lederman, Michael M.; Funderburg, Nicholas T.

doi:10.1097/qai.0000000000000566

Cited by 91 publications

(100 citation statements)

References 50 publications

(68 reference statements)

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“…Chronic innate immune activation in ART-treated HIV infection[26] may promote increases in LDL levels by altering how lipids are processed and transported, and immune activation likely enhances modification of these increased lipid molecules through the activity of reactive oxygen species (ROS) or enzymes such as lipoprotein-associated phospholipase A2 (Lp-PLA 2 )[57], rendering them more “inflammatory.” Modified lipid species, including oxidized forms of LDL (oxLDL)[58, 59] and HDL (HDLox) [60, 61], may contribute directly to monocyte[62] and endothelial cell activation in HIV disease, placing them on the mechanistic pathway for increased inflammation, immune activation, and CVD risk. Results from the ACTG substudy A5260s demonstrate that levels oxidized HDL are related to markers of inflammation and immune activation at baseline (IL-6, hsCRP, %CD38+HLA-DR+CD8+ T cells, sCD163) and following 96 weeks of ART (markers as before, including sCD14) [63].…”

Section: Introductionmentioning

confidence: 99%

Lipid Abnormalities and Inflammation in HIV Inflection

2016

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Infection with the human immunodeficiency virus (HIV), and subsequent treatment with antiretroviral therapy (ART), is often associated with perturbations in lipid profiles. Furthermore, persistent inflammation, in spite of suppression of viral replication by ART, likely contributes to modifications in lipid composition and function, exacerbating risk for development of cardiovascular disease (CVD). Increased levels of several pro-inflammatory lipid species, including oxidized LDL and HDL, have been measured in HIV-infected persons and are associated with markers of immune activation. The mechanisms linked to this bidirectional relationship in which inflammation increases lipid levels and promotes their modification, and these modified lipid species perpetuate inflammatory processes, require further investigation. Treatment with statins and other lifestyle modifications, including improvement in dietary intake and exercise, are critical to reducing CVD risk. Well-designed clinical trials that take into account the complex relationships among lipids and inflammation within persons infected with HIV need to be considered.

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Section: Introductionmentioning

confidence: 99%

Lipid Abnormalities and Inflammation in HIV Inflection

2016

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“…As early HIV-1 infection is characterized by persistent inflammation and enhanced tryptophan catabolism (22,(24)(25)(26)(27)42), we first evaluated the levels of several proinflammatory molecules and Kyn in plasma from the PHI, CHI, and HIV free subjects. Consistent with earlier reports (22,25,43), we found higher levels of IL-6, sCD14, IP-10, and Kyn in PHI and CHI subjects than HIV free donors (Fig.…”

Section: Loss Of Memory Cd4 T Cells During Hiv-1 Infection Involves Dmentioning

confidence: 99%

“…This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptophan into kynurenine (Kyn), which is mediated by the indoleamine 2,3-dioxygenase 1 (IDO-1) expressed in dendritic cells (DCs) and monocytes, is increased in HIV-1-infected subjects (22,(28)(29)(30).…”

mentioning

confidence: 99%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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“…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 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].…”

Section: Comorbid Conditionsmentioning

confidence: 99%

“…Zidar et al showed that HIV-infected patients have both increased plasma levels of 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].…”

Section: Comorbid Conditionsmentioning

confidence: 99%