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

October 26, 1999
96 (22) 12766-12771

Abstract

Endocytosis of the Flaviviridae viruses, hepatitis C virus, GB virus C/hepatitis 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 lipoprotein/LDL 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.

Continue Reading

Acknowledgments

We are grateful to Dr. Marc S. Collett for providing BVDV reagents and advice, Dr. Ruben O. Donis for providing the CRIB cell line, Dr. Charles A. Dinarello for helpful discussions, and Polly Zorolow for editing. This study was supported in part by the Robert E. Wise, M.D., Research and Education Institute, Lahey Clinic Medical Center, Burlington, MA, and National Institutes of Health Grant 1R21AI40672.

References

1
V Agnello, R T Chung, L M Kaplan N Engl J Med 327, 1490–5 (1992).
2
V Agnello Springer Semin Immunopathol 19, 111–129 (1997).
3
V Agnello, G Ábel Arthritis Rheum 40, 2007–2015 (1997).
4
G Monti, M Galli, F Invernizzi, P Pioltelli, F Saccardo, A Monteverde, M Pietrogrande, P Renoldi, S Bombardieri, G Bordin Q J Med 88, 115–26 (1995).
5
R Thomssen, S Bonk, C Propfe, K H Heermann, H G Kochel, A Uy Med Microbiol Immunol 181, 293–300 (1992).
6
A M Prince, T Huima-Byron, T S Parker, D M Levine J Viral Hepat 3, 11–17 (1996).
7
V Agnello, J L Barnes J Exp Med 164, 1809–1814 (1986).
8
K S Arnold, T Inneratiry, R Pitas, R Mahley Lipoprotein Analysis: A Practical Approach, eds C A Converse, E R Skinner (IRL, Oxford), pp. 145–168 (1992).
9
B B Knowles, C C Howe, D P Aden Science 209, 497–499 (1980).
10
G B Knight, V Agnello, V Bonagura, J L Barnes, D J Panka, Q X Zhang J Exp Med 178, 1903–1911 (1993).
11
C F Yen, C I Kalunta, F S Chen, J S Kaptein, C K Lin, P M Lad J Immunol Methods 177, 55–67 (1994).
12
V Agnello, G Ábel, G B Knight, E Muchmore Hepatology 28, 573–584 (1998).
13
F Liu, G B Knight, G Ábel, V Agnello J Virol Methods 79, 149–159 (1999).
14
C Pellerin, J van den Hurk, J Lecomte, P Tussen Virology 203, 260–268 (1994).
15
J Shepherd, S Bicker, A R Lorimer, C J Packard J Lipid Res 20, 999–1006 (1979).
16
L C Kreutz, M R Ackermann Virus Res 42, 137–147 (1996).
17
R Subramanian, H Hiroaki, T M Kashyp J Lab Clin Med 125, 479–485 (1995).
18
K H Weisgraber, T L Innerarity, K J Harder, R W Mahley, R W Milne, Y L Marcel, J T Sparrow J Biol Chem 258, 12348–12354 (1983).
19
R J Pease, R W Milne, W K Jessup, A Law, P Provost, J-C Fruchart, R T Dean, Y L Marcel, J Scott J Biol Chem 265, 553–568 (1990).
20
Y L Marcel, P R Provost, H Koa, E Raffai, N V Dac, J-C Fruchart, E Rassart J Biol Chem 266, 3644–3653 (1991).
21
R W Mahley, T L Innerarity, R E Pitas, K H Weisgraber, J H Brown, E Gross J Biol Chem 252, 7279–7287 (1977).
22
P A Nuttall, P D Luther, E J Stott Nature (London) 266, 835–837 (1977).
23
M Yanagi, J Bukh, S U Emerson, R H Purcell J Infect Dis 174, 1324–1327 (1996).
24
E F Flores, R O Donis Virology 208, 565–575 (1995).
25
K Sato, T Tanaka, H Okamoto, Y Miyakawa, M Mayumi Biochem Biophys Res Commun 229, 719–725 (1996).
26
S Seipp, H M Mueller, E Pfaff, W Stremmel, L Theilmann, T Goeser J Gen Virol 78, 2467–2476 (1997).
27
M Monazahian, I Bohme, S Bouk, A Koch, C Scholz, S Grethe, R Thomssen J Med Virol 57, 223–229 (1999).
28
D G Fischer, N Tal, D Novick, S Barak, M Rubinstein Science 262, 250–253 (1993).
29
B J Mills, D P Beebe, N R Cooper J Immunol 123, 2518–2524 (1979).
30
H Tilg, J W Mier, W Vogel, W E Aulitzky, C J Wiedermann, E Vannier, C Huber, C A Dinareello J Immunol 150, 4687–4692 (1993).
31
C A Dinarello Blood 87, 2095–2147 (1996).
32
F Hofer, M Gruenberger, H Kowalski, H Machat, M Huettinger, E Kuechler, D Blaas Proc Natl Acad Sci USA 91, 1839–1842 (1994).
33
P Bates, J A Young, H E Varmus Cell 74, 1043–1051 (1993).

Information & Authors

Information

Published in

The cover image for PNAS Vol.96; No.22
Proceedings of the National Academy of Sciences
Vol. 96 | No. 22
October 26, 1999
PubMed: 10535997

Classifications

Submission history

Received: November 25, 1998
Published online: October 26, 1999
Published in issue: October 26, 1999

Acknowledgments

We are grateful to Dr. Marc S. Collett for providing BVDV reagents and advice, Dr. Ruben O. Donis for providing the CRIB cell line, Dr. Charles A. Dinarello for helpful discussions, and Polly Zorolow for editing. This study was supported in part by the Robert E. Wise, M.D., Research and Education Institute, Lahey Clinic Medical Center, Burlington, MA, and National Institutes of Health Grant 1R21AI40672.

Authors

Affiliations

Vincent Agnello
Lahey Clinic Medical Center, Department of Laboratory Medicine, Burlington, MA 01805; and Edith Nourse Rogers Memorial Veterans Affairs Hospital, Bedford, MA 01730
György Ábel
Lahey Clinic Medical Center, Department of Laboratory Medicine, Burlington, MA 01805; and Edith Nourse Rogers Memorial Veterans Affairs Hospital, Bedford, MA 01730
Mutasim Elfahal
Lahey Clinic Medical Center, Department of Laboratory Medicine, Burlington, MA 01805; and Edith Nourse Rogers Memorial Veterans Affairs Hospital, Bedford, MA 01730
Glenn B. Knight
Lahey Clinic Medical Center, Department of Laboratory Medicine, Burlington, MA 01805; and Edith Nourse Rogers Memorial Veterans Affairs Hospital, Bedford, MA 01730
Qing-Xiu Zhang
Lahey Clinic Medical Center, Department of Laboratory Medicine, Burlington, MA 01805; and Edith Nourse Rogers Memorial Veterans Affairs Hospital, Bedford, MA 01730

Notes

To whom reprint requests should be addressed at: Department of Laboratory Medicine, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805. E-mail: [email protected].
Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved August 24, 1999

Metrics & Citations

Metrics

Note: The article usage is presented with a three- to four-day delay and will update daily once available. Due to ths delay, usage data will not appear immediately following publication. Citation information is sourced from Crossref Cited-by service.


Citation statements

Altmetrics

Citations

Export the article citation data by selecting a format from the list below and clicking Export.

Cited by

    Loading...

    View Options

    View options

    PDF format

    Download this article as a PDF file

    DOWNLOAD PDF

    Login options

    Check if you have access through your login credentials or your institution to get full access on this article.

    Personal login Institutional Login

    Recommend to a librarian

    Recommend PNAS to a Librarian

    Purchase options

    Purchase this article to access the full text.

    Single Article Purchase

    Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor
    Proceedings of the National Academy of Sciences
    • Vol. 96
    • No. 22
    • pp. 12211-12970

    Figures

    Tables

    Media

    Share

    Share

    Share article link

    Share on social media