Ineffectual immunity in a resurrected mouse model of persistent viremia

Viruses that establish persistent (i.e., chronic) infection have evolved
sophisticated strategies to avoid clearance by the host immune system.
This is particularly true for viruses that infect immunocompetent mammals
and sustain high infectious burdens in body sites under intense immune
surveillance (i.e., the blood, a.k.a., “viremia”). Historically,
lymphocytic choriomeningitis virus (LCMV) infection of laboratory mice has
served as a powerful model to understand mechanisms of failed immunity,
but other viruses may have unique and underappreciated persistence
strategies. Here, we resurrect a bygone model of viral
persistence––lactate dehydrogenase-elevating virus (LDV)––and use modern
transgenic mouse technologies to investigate various aspects of anti-viral
immunity. We find that interferons have a modest impact on LDV
replication, with interferon-alpha blunting LDV viremia in the acute phase
of the infection and interferon-gamma reducing LDV viral loads in the
chronic phase of infection, but only when paired with an intact
interferon-alpha response. Adaptive immunity, assessed in Rag-knockout
mice, had only a modest impact on LDV viremia, and only during the
sub-acute phase of infection. Mice lacking the critical immune checkpoint
molecule PD-1 showed no signs of disease and supported LDV viral loads at
levels equivalent to their wild-type counterparts. Altogether, these
results point to a novel and highly effective mechanism of persistence
that is minimally impacted by conventional aspects of anti-viral immunity
or immune exhaustion––a rarity among persistent viruses. Given the
relative paucity of chronic infection models in the laboratory mouse, LDV
infection may be useful for exploring unique modes of immune system
failure.