Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor

Abstract

Endocytosis of the Flaviviridae viruses, hepatitis C virus, GB virus C͞hepatitis G virus, and bovine viral diarrheal virus (BVDV) was shown to be mediated by low density lipoprotein (LDL) receptors on cultured cells by several lines of evidence: by the demonstration that endocytosis of these virus correlated with LDL receptor activity, by complete inhibition of detectable endocytosis by anti-LDL receptor antibody, by inhibition with anti-apolipoprotein E and -apolipoprotein B antibodies, by chemical methods abrogating lipoprotein͞LDL receptor interactions, and by inhibition with the endocytosis inhibitor phenylarsine oxide. Confirmatory evidence was provided by the lack of detectable LDL receptor on cells known to be resistant to BVDV infection. Endocytosis via the LDL receptor was shown to be mediated by complexing of the virus to very low density lipoprotein or LDL but not high density lipoprotein. Studies using LDL receptor-deficient cells or a cytolytic BVDV system indicated that the LDL receptor may be the main but not exclusive means of cell entry of these viruses. Studies on other types of viruses indicated that this mechanism may not be exclusive to Flaviviridae but may be used by viruses that associate with lipoprotein in the blood. These findings provide evidence that the family of LDL receptors may serve as viral receptors. H epatitis C virus (HCV), the principal viral cause of chronic hepatitis, is not readily replicated in cell culture systems, and, as yet, no information on cell receptors for the virus is available. However, several observations from studies on the role of HCV in mixed cryoglobulinemia (1-3) have provided some insights to HCV entry into cells.Mixed cryoglobulinemia is a systemic vasculitis associated with cold-precipitable immunoglobulins in the blood. During the past 5 years, a strong association of HCV infection with mixed cryoglobulins has been established (4), and the specific concentration of HCV in type II mixed cryoglobulins that consist of polyclonal IgG and monoclonal IgM has been demonstrated (1). It also was shown that very low density lipoprotein (VLDL) is selectively associated with HCV in type II cryoglobulins (2). In studies on the cutaneous vasculitic lesions in type II cryoglobulinemia using in situ hybridization (ISH), the HCV RNA virion form (positive strand) but not the putative replicative form (negative strand) of the virus was detected in keratinocytes in lesions but not normal skin of the same patients (3). Furthermore, it was demonstrated that LDL receptors were upregulated on keratinocytes in cutaneous vasculitis lesions compared with normal skin (3). These observations and the finding that anti-␤ lipoprotein precipitates HCV from infected serum (5) suggested that the low density lipoprotein (LDL) receptor also may be a receptor for HCV complexed to VLDL or LDL. This hypothesis led to this study to determine whether the LDL receptor is also a receptor for HCV and other members of the family of viruses Flaviviridae. Materials and Methods

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…An obvious example is the ability of viruses to bind certain receptors expressed by specific cell types to facilitate cell entry, and subsequently utilize intracellular machineries for nucleotide and protein production. 71,72 In addition, some viruses encode proteins that share structural and functional similarities with host molecules, such as herpes and myxoma viruses, that mimic anti-apoptotic protein BCL-2 to prolong viral replication before the initiation of hostprogrammed cell death. 73 Not surprisingly, pathogens including bacteria, viruses, fungi and oomycetes also exploit the host's phospholipid code for a variety of functions during an infection (Table 1).…”

Entry and replication of recombinant hepatitis C viruses in cell culture

“…Moreover, host factors crucial for production of VLDL like apolipoprotein E, apolipoprotein B and microsomal triglyceride transfer protein have been found to be important for production and release of infectious HCV particles [24][25][26][27][28][29]. The association of HCV with lipoproteins influences cell entry with the involvement of several lipoprotein (LDL receptor) [30,31] and lipid receptors (Scavenger receptor class B type I, SR-BI; Niemann-Pick C1-like 1 cholesterol uptake receptor, NPC1L1) [32,33]. It might also contribute to protect the virus from the host humoral immune response.…”

“…Anti-E1/E2 Abs [9,11,62,148], patient sera [9], soluble E2 [46], lectins [150,151], anti-ApoE antibodies [29], apoE peptides [149] Abs, Erlotinib, Lapatinib, Gefitinib [141] EGF, TGF-α [141] HDL [138] ApoCI [139] BLTs [138,140] Abs, Dasatinib [141] Arbidol [144] Abs [109,137], ITX 5061 [134], natural ligands [135,136] Abs, soluble CD81 [9,11] Abs [142] Cldn1 peptide [143] Heparin, GAG nzymatic digestion [69,132] Abs, natural ligands, soluble LDL receptor [30,133] GAGs LDLR CD81 SR-BI Cldn1 Ocln…”

“…Reporter protein Abs [109,137], ITX 5061 [134], natural ligands [135,136] Abs, soluble CD81 [9,11] Abs [142] Cldn1 peptide [143] Heparin, GAG nzymatic digestion [69,132] Abs, natural ligands, soluble LDL receptor [30,133] GAGs LDLR CD81 SR-BI Cldn1 Ocln…”

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection

“…Two molecules have been proposed to function as HCV receptors, namely the low density lipoprotein receptor (LDLR) and CD81. [3][4][5] The LDLR gene family has been shown to function as a receptor for the minor-group common cold virus and for the subgroup A Rous sarcoma virus previously. 6,7 The LDLR is known to play an important role in cholesterol homeostasis and lipid transport by mediating the cellular uptake of plasma LDL.…”