Early antibodies specific for the neutralizing epitope on the receptor binding subunit of the lymphocytic choriomeningitis virus glycoprotein fail to neutralize the virus.
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.
Eschli
Bruno
B
Institute of Experimental Immunology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland. bruno.eschli@bluewin.ch
Zellweger
Raphaël M
RM
Wepf
Alexander
A
Lang
Karl S
KS
Quirin
Katharina
K
Weber
Jacqueline
J
Zinkernagel
Rolf M
RM
Hengartner
Hans
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000914:Antibodies, Viral / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry*; D006023:Glycoproteins / Q000737:chemistry; D008216:Lymphocytic Choriomeningitis / Q000517:prevention & control / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D009698:Nucleoproteins / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000939:Epitopes; D006023:Glycoproteins; D009698:Nucleoproteins
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