Viruses elicit a broad spectrum of antibody responses. By focusing on two experimental virus infections — the non-cytopathic, persistency-prone lymphocytic choriomeningitis virus (LCMV) and the acutely cytopathic, rabies-like vesicular stomatitis virus (VSV) in mice — we outline two fundamentally different types of antiviral antibody response. These results are discussed in the context of other viral infections, such as influenza virus and HIV.
The immunogenicity of viral surface proteins is influenced by various factors, including accessibility, glycosylation, repetitiveness and organization. The availability of B cells that encode immunoglobulin that is specific for these different viral epitopes also has a great impact on their immunogenicity.
Acutely cytopathic virus infections, such as VSV, must be controlled rapidly before the virus can spread to vital organs and kill the host. Therefore, most cytopathic viruses support the rapid generation of neutralizing antibodies.
Poorly or non-cytopathic viruses, such as LCMV, tend to persist and actively interfere with the generation of neutralizing antibodies. These viruses are frequently transmitted vertically from a virus-carrier mother to her immuno-incompetent offspring.
Spleen and bone marrow have a limited capacity to accommodate antibody-producing plasma cells. However, IgM has a short serum half-life, and protective IgM titres require many plasma cells to be maintained. The longer serum half-life of IgG isotype class-switched antibodies allows protective titres to be maintained by fewer plasma cells. In addition, IgG antibodies can be transferred to the infant for protection during the early period of immunoincompentence.
There is evidence that germline-encoded antibodies can provide early and sufficient protection against cytopathic viruses, without undergoing somatic hypermutation (SHM). By contrast, extensive SHM and affinity maturation are required for the formation of protective humoral responses against poorly cytopathic viruses that have a tendency to persist. In these cases, the germline repertoire does not normally provide antibodies with sufficient affinity to be immediately protective.
Viruses tend to escape neutralizing antibody responses. In general, rapidly transmitting, acutely cytopathic, and therefore lethal, viruses have to evade herd immunity and therefore frequently exist in closely related but immunologically distinct varieties (serotypes). By contrast, poorly cytopathic viruses evade the immune response of the individual host by diversifying into numerous quasi-species, with individual neutralizing specificities within a single infected individual.
Viruses elicit a diverse spectrum of antiviral antibody responses. In this review, we discuss two widely used experimental model systems for viral infections — non-cytopathic lymphocytic choriomeningitis virus (LCMV) and acutely cytopathic vesicular stomatitis virus (VSV) — to analyse two fundamentally different types of antiviral antibody response. The basic principles found in these model infections are discussed in the context of other viral infections, and with regard to protective neutralizing versus non-protective enzyme-linked immunosorbent assay (ELISA)-detected antibody responses. Issues of antibody specificity, affinity and avidity, maturation and escape are discussed in the context of co-evolution of the host and viruses.
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We are grateful to B. Eschli for sharing unpublished data regarding the LCMV-glycoprotein-specific antibody response in wild-type mice and for helpful discussions during the preparation of the manuscript. We also thank K. McCoy and N. Harris for critical reading of the manuscript, together with A. Trkola, M. Recher, H.C. Probst, K. Fink and R. Zellweger for discussions and reading of the manuscript.
The authors declare no competing financial interests.
Reversible dormant state of viruses in infected cells with minimal production of viral proteins and absence of progeny virus production.
- Complementarity-determining region
(CDR). The most variable parts of immunoglobulin molecules and T-cell receptors. These regions form loops that make contact with specific ligands. There are three such regions (CDR1, CDR2 and CDR3) contained in each V domain, with CDR3 arising from V(D)J rearrangement, and therefore being the most variable CDR.
- T-cell-independent antigen/T-cell-dependent antigen
Antigens that require specific T-cell help for eliciting antibody responses are designated as T-cell-dependent antigens. By contrast, T-cell-independent antigens elicit IgM antibody responses in the absence of specific T-cell help.
The part of an antigen that is directly recognized by antibodies or T-cell receptors.
(Enzyme-linked immunosorbent assay). This assay can be used to detect antibodies that bind to an antigen, which is immobilized on a plastic surface. Samples to be tested are incubated on the coated plastic plates to allow binding of the contained antibodies to the coated antigen. Bound antibodies are then detected through an anti-immunoglobulin antibody coupled to an enzyme, which can catalyse a colour reaction.
- Neutralization assay
An in vitro assay used to detect direct antiviral activities of antibodies. Constant amounts of infectious virus are incubated with serially diluted antibodies and neutralizing titres are defined as the dilution that reduces infectivity in cell cultures by at least 50%.
A small molecule, or part of a molecule, that can elicit antibody responses when it is chemically linked to a carrier, but that is not immunogenic by itself. B-cell responses against haptens require priming of T-helper cells that are specific for the carrier, unless they are repetitively linked to a rigid carrier at a distance of 5–10 nm.
- B-cell superantigen
Antigen that is able to activate B cells by signalling through the B-cell receptor, irrespective of the specificity of its immunoglobulin component. B-cell superantigens usually bind to areas of immunoglobulin molecules that are not involved in normal antigen recognition.
- On rate/off rate
Binding of a ligand to its receptor (for example, antigen to antibody) is determined by the on-rate, describing the kinetics by which the ligand is bound by the receptor, and the off-rate, describing the kinetics by which bound ligand is released from the receptor. In the equilibrium, the amount of complexed ligand is determined by the ratio between the on- and the off-rate.
- Somatic hypermutation
(SHM). The process by which antigen-activated B cells in germinal centres mutate the rearranged immunoglobulin genes. The B cells are subsequently selected for those that express the 'best' mutations on the basis of the ability of the surface immunoglobulin to bind antigen.
- Long-term non-progressor
(LTNP). There is no universally adopted definition of LTNP, and often LTNP is used interchangeably with HIV controller, because control of viremia is strongly predictive of LNTP. So, LTNP refers to untreated HIV-infected individuals who are infected for more than 10 years, whose CD4+ T-cell counts and viral load are stable over time and who are free of disease.
- Heterologously primed
Hosts that are immune against a different virus or serotype than that used for a secondary infection.
- Antigenic drift
Continuous mutation of surface antigens used by influenza viruses to gain resistance against antibody responses that are elicited by previous, less mutated variants.
- Antigenic shift
Emergence of influenza viruses that use surface antigens that differ fundamentally from those of currently circulating strains. The acquisition of relevant genome segments of avian origin by human influenza viruses is thought to be mainly responsible for these antigenic shifts.
- Original antigenic sin
A term used to describe the phenomenon in which infections with drifted variants of influenza viruses boost memory responses against the virus that has been encountered first.
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Hangartner, L., Zinkernagel, R. & Hengartner, H. Antiviral antibody responses: the two extremes of a wide spectrum. Nat Rev Immunol 6, 231–243 (2006). https://doi.org/10.1038/nri1783
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