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The immune control of mammalian gamma-herpesviruses: lessons from Murid Herpesvirus-4

¹ University of Cambridge;
² University of Lisbon

³ E-mail: pgs27{at}cam.ac.uk

Many acute viral infections can be controlled by vaccination. However, vaccinating against persistent infections remains problematic. Herpesviruses are a classic example. Here we discuss their immune control, particularly that of gamma-herpesviruses, relating the animal model provided by Murid Herpesvirus-4 to human infections. The following points emerge:(1) CD8+ T cell evasion by herpesviruses confers on CD4+ T cells a prominent role in host defence. CD4+ T cells inhibit Murid Herpesvirus-4 lytic gene expression via IFN-. By reducing the lytic secretion of immune evasion proteins, they may also help CD8+ T cells to control virus-driven lymphoproliferation in mixed lytic / latent lesions. Similarly, CD4+ T cells specific for Epstein-Barr virus lytic antigens could improve the impact of adoptively transferred, latent antigen-specific CD8+ T cells.(2) In general, viral immune evasion mandates multiple host effectors for optimal control. Thus sub-unit vaccines, which tend to prime single effectors, have proved less successful than attenuated virus mutants, which prime multiple effectors. Latency-deficient mutants could make safe and effective gamma-herpesvirus vaccines.(3) The antibody response to Murid Herpesvirus-4 infection helps to prevent disease, but is sub-optimal for neutralization. Vaccinating virus carriers with virion fusion complex components improves their neutralization titers. Reducing the infectivity of herpesvirus carriers in this way could be a useful adjunct to vaccinating naive individuals with attenuated mutants.

Received 11 May 2009; accepted 9 July 2009.