PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression #

Abstract

Human PCSK9 is known to enhance the degradation of membrane-bound receptors such as the hepatocyte low-density lipoprotein receptor (LDLR), ApoER2, and very low-density lipoprotein receptor. Because the LDLR is suspected to be involved in hepatitis C virus (HCV) entry, we also tested whether PCSK9 can affect the levels of CD81, a major HCV receptor. Interestingly, stable expression of PCSK9 or a more active membrane-bound form of the protein (PCSK9-ACE2) resulted in a marked reduction in CD81 and LDLR expression. Therefore, we analyzed the antiviral effect of PCSK9 in vitro using the HCV genotype 2a ( H epatitis C virus (HCV) is a worldwide leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. 1 In the absence of a prophylactic vaccine or a specific antiviral agent, the best treatment currently available for HCV infection is the combination therapy of pegylated interferon and ribavirin. 2 HCV is a positive-strand RNA enveloped virus classified as a Hepacivirus within the Flaviviridae family. 3 Viral entry within target cells, primarily human hepatocytes, is not very well understood. Several cell surface proteins have been suggested to play a role in the binding of HCV to hepatocytes and/or be critical for viral entry. 4,5 Among the acknowledged receptors or coreceptors of HCV are: CD81, 6 scavenger receptor class B type I, 7 lowdensity lipoprotein receptor (LDLR), 8 and the recently identified claudin-1, claudin-6, claudin-9, 9 and occludin. 10 However, it is unclear which ones are required for viral propagation in vivo. Indeed, HCV particles recovered from infected plasma migrated at two distinct densities (1.25 g/mL and 1.06 g/mL). 11,12 It has been suggested that the most infectious virus is located in the low-density fraction that corresponds to lipoviroparticles of HCV coated with apolipoprotein B and E. 11 Because LDLR controls the uptake of circulating cholesterol principally through internalization of apolipoprotein B-and E-containing lipoproteins, such as LDL and very low-density lipoprotein, the implication of LDLR as a nonspecific receptor for HCV entry may be significant, at least in vivo.

Dissection of the Endogenous Cellular Pathways of PCSK9-induced Low Density Lipoprotein Receptor Degradation

“…VLDLR and apo-ER2, but not angiotensin-converting enzyme 2 (26) nor the high density lipoprotein receptor SR-BI, hepatocyte growth factor receptor HGFR, or transferrin receptor TfR (27). It was also shown previously that overexpression of PCSK9 in a rat hepatic cell line reduces the levels of LDLR mostly in transfected cells (15).…”

Pcsk9

“…The data showed that PCSK9 targets 2 hepatic HCV receptors for degradation, namely the LDLR and the tetraspanin protein CD81. 71 Furthermore, it was recently reported that other viruses bind to cell surface LDLR family members to enter and infect cells, including vesicular stomatitis virus that likely uses the LDLR and LRP1 as entry receptors. 72 These results suggested that although inhibiting PCSK9 may be beneficial to reduce the levels of circulating LDL-C, it potentially could enhance the infectivity of certain viruses, such as HCV, vesicular stomatitis virus, the common cold rhino virus, and rous sarcoma virus.…”

“…Recently, it was shown that liver expression of CD81 is markedly increased in Pcsk9-knockout mice and that the HCV receptor CD81 protein is downregulated independently from the LDLR. 71 Therefore, it was proposed that the plasma level and activity of PCSK9 could modulate HCV infectivity in humans. In summary, the LDLR and CD81, 2 HCV entry receptors are dose dependently downregulated by PCSK9, resulting in the reduction of the cellular infectivity of HCV in mice.…”

PCSK9: A key factor modulating atherosclerosis

“…Up to 30% of circulating PCSK9 is associated with LDL, regardless of LDLR expression, probably by increasing both the hepatic and intestinal synthesis of apoB, the LDL particle structural protein 21) . Previ- tect against HCV in mice by downregulating the hepatic expression of CD81 and HCV entry receptors, resulting in a decreased HCV cellular infection rate, although this has not been shown in humans 38) . Moreover, PCSK9 deficiency results in delayed hepatocyte proliferation and enhanced apoptosis following partial hepatectomy, which can be rescued by feeding the mice a high-ch olesterol diet 23) .…”