Evidence for cross-genotype neutralization of hepatitis C virus pseudo-particles and enhancement of infectivity by apolipoprotein C1

Abstract

The lack of a cell culture system to support hepatitis C virus (HCV) replication has hampered studies of this frequent cause of chronic liver disease. However, pseudotyped retroviral particles (pp) bearing the HCV envelope glycoproteins have provided a different approach to HCV studies. We used genotype 1a pp to detect neutralizing antibodies (NtAb) in eight chimpanzees and four humans infected with 1a strains, and developed pp of genotypes 2a, 3a, 4a, 5a, and 6a to study cross-reactivity. NtAb was detected in one of four chimpanzees and none of three humans with acute resolving infection, suggesting that NtAb is not required for HCV clearance. NtAb were detected at high titer in two of four chimpanzees and, in Patient H, all with persistent infection; responses paralleled humoral responses to envelope 1 and 2 proteins and, in some cases, correlate also with antibodies to the hypervariable region 1, previously thought to be the primary site of neutralization. NtAb raised during 1a infections could neutralize HCVpp of genotypes 4a, 5a, and 6a but had only limited reactivity against 2a and 3a. The detection of high-titer NtAb with cross-genotype reactivity has important implications for the development of active and passive immune-prophylaxis strategies against HCV. Finally, we found that HCVpp infectivity was enhanced by human or chimpanzee sera; apolipoprotein C1 alone or as a component of high-density lipoproteins caused this enhancement. Future studies of the in vivo role of apolipoprotein C1 might provide additional insights into the infection process of HCV.neutralizing antibodies ͉ high-density lipoproteins

Entry and replication of recombinant hepatitis C viruses in cell culture

“…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…”

“…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] …”

Serum amyloid A has antiviral activity against hepatitis C virus by inhibiting virus entry in a cell culture system

“…Because HDL has been shown to be the major serum component responsible for enhancement of HCVpp infectivity, [10][11][12] we also tested the antiviral activity of SAA in the presence of purified HDL. The inhibitory effect of SAA was strongly attenuated in the presence of this lipoprotein during infection (Fig.…”

“…Interestingly, when HCVpp is incubated in the presence of high-density lipoprotein (HDL), a physiological ligand of SR-BI, infectivity is increased rather than reduced. [10][11][12] In addition, HDL-mediated facilitation of HCVpp entry depends on the lipid transfer property of SR-BI, 10,12 suggesting that HCV exploits the physiological activity of SR-BI for promoting its entry into target cells.…”

Hepatitis C virus comes full circle

“…Thus, HCV entry likely involves transit through an endosomal, low-pH compartment and fusion with the endosomal membrane, a process that has recently been elucidated in great detail in related flaviviruses. 31,32 Retroviral pseudotypes allowed, for example, to validate CD81 as an essential component of the HCV entry pathway [33][34][35] and to investigate the role of neutralizing antibodies in acute and chronic hepatitis C. [36][37][38][39] Despite these advances, robust recapitulation of the entire HCV life cycle in tissue culture remained elusive.…”