Native High-Density Lipoproteins (HDL) with Higher Paraoxonase Exerts a Potent Antiviral Effect against SARS-CoV-2 (COVID-19), While Glycated HDL Lost the Antiviral Activity

Abstract

Human high-density lipoproteins (HDL) show a broad spectrum of antiviral activity in terms of anti-infection. Although many reports have pointed out a correlation between a lower serum HDL-C and a higher risk of COVID-19 infection and progression, the in vitro antiviral activity of HDL against SARS-CoV-2 has not been reported. HDL functionality, such as antioxidant and anti-infection, can be impaired by oxidation and glycation and a change to pro-inflammatory properties. This study compared the antiviral activity of native HDL with glycated HDL via fructosylation and native low-density lipoproteins (LDL). After 72 h of fructosylation, glycated HDL showed a typical multimerized protein pattern with an elevation of yellowish fluorescence. Glycated HDL showed a smaller particle size with an ambiguous shape and a loss of paraoxonase activity up to 51% compared to native HDL. The phagocytosis of acetylated LDL was accelerated 1.3-fold by glycated HDL than native HDL. Native HDL showed 1.7 times higher cell viability and 3.6 times higher cytopathic effect (CPE) inhibition activity against SARS-CoV-2 than that of glycated HDL under 60 μg/mL (approximately final 2.2 μM) in a Vero E6 cell. Native HDL showed EC50 = 52.1 ± 1.1 μg/mL (approximately final 1.8 μM) for the CPE and CC50 = 79.4 ± 1.5 μg/mL (around 2.8 μM). The selective index (SI) of native HDL was calculated to be 1.52. In conclusion, native HDL shows potent antiviral activity against SARS-CoV-2 without cytotoxicity, while the glycation of HDL impairs its antiviral activity. These results may explain why patients with diabetes mellitus or hypertension are more sensitive to a COVID-19 infection and have a higher risk of mortality.

Clinical Performance of Paraoxonase-1-Related Variables and Novel Markers of Inflammation in Coronavirus Disease-19. A Machine Learning Approach

“…The little data existing seems to suggest two different roles for PON1 in COVID-19, depending on whether it is present in the circulation or within cells. Purified native HDL with intact PON1 elicits a potent antiviral effect against SARS-CoV-2 in cultured monocyte cells, while glycated HDL, with inactive PON1, loses the antiviral activity [ 24 ]. However, an in silico study reported that PON1 enhances the action of ACE2, the main cell receptor of SARS-CoV-2 [ 25 ], and the inhibition of PON1 activity has been reported as a potent inhibitor of vaccinia virus protein synthesis and viral mRNA methylation in mice [ 26 ], suggesting that intracellular PON1 is important in the translation of viral proteins and virus replication.…”

Decreased Low-Density Lipoprotein Cholesterol Level Indicates Poor Prognosis of Severe and Critical COVID-19 Patients: A Retrospective, Single-Center Study

“…Studies have shown that HDL-C can regulate innate and adaptive immunity, thereby increasing resistance to viral infections ( 31 ). In addition, a recent study showed that HDL-C has antiviral activity against SARS-CoV-2 ( 32 ). Decreased HDL-C levels during hospitalization have been reported as a sign of poor prognosis for COVID-19 patients ( 27 ).…”

The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions

“…A decreased content in PON1 and an increased content of SAA and alpha-1 antitrypsin compared to control subjects are associated with impaired ability of HDL-mediated to inhibit the apoptosis of endothelial cells [ 122 ]. In vitro, glycation impairs the inhibitory activity of HDL towards SARS-CoV-2 infection of epithelial cells [ 153 ]. Whether or not infection of endothelial cells with SARS-CoV2 is inhibited by HDL and disturbed by glycation remains to be investigated.…”