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Journal of Virology, November 2007, p. 11650-11657, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00955-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Early Antibodies Specific for the Neutralizing Epitope on the Receptor Binding Subunit of the Lymphocytic Choriomeningitis Virus Glycoprotein Fail To Neutralize the Virus

Bruno Eschli,^1*, Raphaël M. Zellweger,^1, Alexander Wepf,¹ Karl S. Lang,¹ Katharina Quirin,² Jacqueline Weber,¹ Rolf M. Zinkernagel,¹ and Hans Hengartner¹

Institute of Experimental Immunolgy, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland,¹ Institute of Biochemistry, ETH Zürich, Schafmattstrasse 18, Switzerland²

Received 3 May 2007/ Accepted 7 August 2007

Lymphocytic choriomeningitis virus (LCMV) is a murine arenavirus whose glycoprotein consists of a transmembrane subunit (GP-2) and a receptor-binding subunit (GP-1). LCMV-neutralizing antibodies (nAbs) are directed against a single site on GP-1 and occur 1 month after the infection of cytotoxic-T-lymphocyte (CTL) deficient mice. In wild-type mice, however, CTLs control early infection, and weak nAb titers emerge very late (after 70 to 150 days) if at all. Production of recombinant GP-1 in native conformation enabled us to study the emergence of GP-1-binding antibodies directed against the neutralizing epitope. By combining binding and neutralization assays, we correlated the development of binding antibodies versus nAbs in wild-type and CTL-deficient mice after infection with different LCMV doses. We found that wild-type mice developed GP-1-specific antibodies already by day 8 after exposure to high but not low doses, demonstrating that naive GP-1-specific B cells were infrequent. Furthermore, the induced antibodies bound to the neutralizing GP-1 epitope but failed to neutralize the virus and therefore were of low affinity. In CTL-deficient mice, where massive viremia quickly levels initial differences in viral load, low and high doses induced low-affinity non-neutralizing GP-1-binding antibodies with kinetics similar to high-dose-infected wild-type mice. Only in CTL-deficient mice, however, the GP-1-specific antibodies developed into nAbs within 1 month. We conclude that LCMV uses a dual strategy to evade nAb responses in wild-type mice. First, LCMV exploits a "hole" in the murine B-cell repertoire, which provides only a small and narrow initial pool of low-affinity GP-1-specific B cells. Second, affinity maturation of the available low-affinity non-neutralizing antibodies is impaired.

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* Corresponding author. Mailing address: Institute of Experimental Immunology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland. Phone: 0041 (0)44 255 2734. Fax: 0041 (0)44 255 4420. E-mail: bruno.eschli{at}bluewin.ch

Published ahead of print on 15 August 2007.

B.E. and R.M.Z. contributed equally to this study.

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Journal of Virology, November 2007, p. 11650-11657, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00955-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.