Vaccination against gamma-herpesviruses. (360G-Wellcome-076956_Z_05_A)

The gamma-herpesviruses are archetypal persistent parasites. Host immunity fails to prevent the long-term infectivity of virus carriers, presenting a major challenge to disease control. To make progress, we must use animal models to learn more about the fundamental biology of persistent infection. We want to know why virus-specific antibody, which neutralizes infectivity in vitro, fails to do so in vivo. If antibody could be made to neutralize secreted virions, viral transmission would cease.Mechanisms of immune control are difficult to analyze with human gamma-herpesviruses, so we are using the murid virus, MHV-68, to establish basic principles of gamma-herpesvirus infection control. Preliminary data indicate that truly neutralizing specificities are rare in the antibody response to MHV-68. Immune sera serve mainly to divert virions into cells bearing IgG Fc receptors, which then become productively infected. Virion / antibody complexes may even constitute the normal infectious particle.We will determine how rare, neutralizing monoclonal antibodies work, what happens to virion / antibody complexes in vivo, whether boosting the response to neutralization targets can increase the neutralizing activity of immune sera; and whether this improves infection control. We will then use the closely related Kaposi's Sarcoma-associated Herpesvirus, to adapt this experimental strategy of infection control to a clinical setting.