Impaired Antibody Response Causes Persistence of Prototypic T Cell–Contained Virus

Abstract

CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LCMV), a prototypic mouse model of systemic persistent infection. Mice expressing transgenic B cell receptors of LCMV-unrelated specificity, and mice unable to produce soluble immunoglobulin M (IgM) exhibited protracted viremia or failed to resolve LCMV. Virus control depended on immunoglobulin class switch, but neither on complement cascades nor on Fc receptor γ chain or Fc γ receptor IIB. Cessation of viremia concurred with the emergence of viral envelope-specific antibodies, rather than with neutralizing serum activity, and even early nonneutralizing IgM impeded viral persistence. This important role for virus-specific antibodies may be similarly underappreciated in other primarily T cell–controlled infections such as HIV and hepatitis C virus, and we suggest this contribution of antibodies be given consideration in future strategies for vaccination and immunotherapy. Persistent viruses such as hepatitis C virus (HCV) or HIV can defeat the body's defense system and cause devastating epidemics worldwide. Recent attempts at vaccinating against HIV have relied on the induction of specific antiviral killer T lymphocytes but have failed to confer protection on the host. Better knowledge about how a successful defense should operate is therefore essential for developing and refining new vaccines. Here, we have used a prototypic mouse model to investigate basic defense mechanisms required to eliminate persisting viruses. Experiments in several genetically engineered mouse models show that contrary to common belief, not only antiviral killer T cells, but also antibodies (produced by B cells), are needed to prevent a virus from persisting in its host. These findings suggest that induction of antibodies, along with antiviral killer T lymphocytes, should be envisaged when devising new strategies for vaccinating against HIV or HCV.