Apolipoprotein(a) inhibits hepatitis C virus entry through interaction with infectious particles

Abstract

The development of different cell culture models has greatly contributed to increased understanding of the hepatitis C virus (HCV) life cycle. However, it is still challenging to grow HCV clinical isolates in cell culture. If overcome, this would open new perspectives to study HCV biology, including drug‐resistant variants emerging with new antiviral therapies. In this study we hypothesized that this hurdle could be due to the presence of inhibitory factors in patient serum. Combining polyethylene glycol precipitation, iodixanol gradient, and size‐exclusion chromatography, we obtained from HCV‐seronegative sera a purified fraction enriched in inhibitory factors. Mass spectrometric analysis identified apolipoprotein(a) (apo[a]) as a potential inhibitor of HCV entry. Apo(a) consists of 10 kringle IV domains (KIVs), one kringle V domain, and an inactive protease domain. The 10 KIVs are present in a single copy with the exception of KIV type 2 (KIV2), which is encoded in a variable number of tandemly repeated copies, giving rise to numerous apo(a) size isoforms. In addition, apo(a) covalently links to the apolipoprotein B component of a low‐density lipoprotein through a disulfide bridge to form lipoprotein(a). Using a recombinant virus derived from the JFH1 strain, we confirmed that plasma‐derived and recombinant lipoprotein(a) as well as purified recombinant apo(a) variants were able to specifically inhibit HCV by interacting with infectious particles. Our results also suggest that small isoforms are less inhibitory than the large ones. Finally, we observed that the lipoprotein moiety of HCV lipoviroparticles was essential for inhibition, whereas functional lysine‐binding sites in KIV7, KIV8, and KIV10 were not required. Conclusions: Our results identify apo(a) as an additional component of the lipid metabolism modulating HCV infection. (Hepatology 2017;65:1851‐1864)

HDL cholesterol levels and susceptibility to COVID-19

“…41 Apo-A1, an important component of HDL, is shown to inhibit viral fusion and entry into host cells. 42 Taken together, these data support our findings that increased serum HDL-C may to be protective against SARS-CoV-2 infection.…”

Molecular Deformation Is a Key Factor in Screening Aggregation Inhibitor for Intrinsically Disordered Protein Tau

“…In order to reveal the optimized molecular structures and unique electronic properties of the four isatin-pyrrolidinylpyridine compounds, we next conducted density functional theory calculations using Gauss 09 software at the B3LYP/6-31G level . By structural optimization, we find that twisted structure exists in all four isomers; however, high twisting exists in IPP1, which can be simply explained by the increase in steric hindrance . As for the distribution of electrons in molecules, it can be seen that only in IPP1 does the HOMO electron cloud extend to the carbonyl group in five-membered ring A of the isatin moiety while in the other isomers (IPP2–IPP4) the HOMO electron cloud is spread over the whole molecular skeleton, with a weak delocalization over five-membered ring A of the isatin moiety (Figure S13).…”

“…28 By structural optimization, we find that twisted structure exists in all four isomers; however, high twisting exists in IPP1, 29 which can be simply explained by the increase in steric hindrance. 30 As for the distribution of electrons in molecules, it can be seen that only in IPP1 does the HOMO electron cloud extend to the carbonyl group in five-membered ring A of the isatin moiety while in the other isomers (IPP2− IPP4) the HOMO electron cloud is spread over the whole molecular skeleton, with a weak delocalization over fivemembered ring A of the isatin moiety (Figure S13). 31 Meanwhile, the LUMO electron cloud in IPP1 is distributed on both five-membered ring A in the isatin moiety and pyridine ring C in the pyrrolidinylpyridine moiety, indicating a stronger interaction between the two sections.…”

A Comparative Analysis of the Lipoprotein(a) and Low-Density Lipoprotein Proteomic Profiles Combining Mass Spectrometry and Mendelian Randomization

“…Apo(a) has also been shown to inhibit hepatitis C virus invasion through interaction with infectious particles 6 Proteins other than apo(a) or apoB may also be carried by Lp(a) in the plasma, some of which were previously identified by von Zychlinski et al 7 . It appears that the role of these newly identified proteins extends beyond lipoprotein metabolism and may include wound healing and complement activation.…”