Abstract
Herpesvirus carriers transmit infection despite making virus-specific antibodies. Thus, their antibody responses are not necessarily optimal. An important question for infection control is whether vaccinating carriers might improve virus neutralization. The antibody response to murine gamma-herpesvirus-68 (MHV-68) blocks cell binding, but fails to block and even enhances an IgG Fc receptor-dependent infection of myeloid cells. Viral membrane fusion therefore remains intact. Although gH/gL-specific monoclonal antibodies can block infection at a post-binding step close to membrane fusion, gH/gL is a relatively minor antibody target in virus carriers. We show here that gH/gL-specific antibodies can block both Fc receptor-independent and Fc receptor-dependent infections, and that vaccinating virus carriers with a gH/gL fusion protein improves their capacity for virus neutralization both in vitro and in vivo. This approach has the potential to reduce herpesvirus transmission.
Highlights
Persistent viruses have evolved to co-exist with established host immunity
A blockade of cell binding by immune serum neutralizes murine gamma-herpesvirus-68 (MHV-68) for infection of FcR2 cells, but not Fc receptor (FcR)+ cells [17]
We first sought to establish whether gH/gL-specific Monoclonal antibodies (mAbs) could block FcR-dependent infection (Fig. 1)
Summary
Persistent viruses have evolved to co-exist with established host immunity. Herpesviruses are among the most successful, and provide an archetype for many of the immune evasion mechanisms that underlie effective persistence [1,2,3]. In contrast to the plethora of information about T cell evasion, relatively little is known about how herpesviruses evade neutralization by antibody They must do so, since they continue to transmit infection despite eliciting virus-specific antibodies; by contrast, preexisting antibodies generally block the transmission of nonpersistent viruses. Gamma-herpesviruses colonize their hosts mainly by latency-associated lymphoproliferation [14,15,16] This may explain why they do not encode FcRs. Yet gamma-herpesvirus must still evade neutralization. By diverting virions into myeloid cells, antibody should damp down MHV-68 lytic infection even when it fails to achieve neutralization It is the need for transmission rather than the capacity to cause disease that drives viral evolution. If gH/gL-specific antibodies can block FcR-dependent infection, a weak gH/gL-specific response might be crucial to viral evasion of neutralization, and inducing stronger gH/gL-specific immunity might be a means of reducing viral spread.
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