Determinants of Pegivirus persistence, cross-species infection, and adaptation in the laboratory mouse

Viruses capable of causing persistent infection have developed
sophisticated mechanisms for evading host immunity, and understanding
these processes can reveal novel features of the host immune system. One
such virus, human pegivirus (HPgV), infects ~15% of the global human
population, but little is known about its biology beyond the fact that it
does not cause overt disease. We passaged a pegivirus isolate of feral
brown rats (RPgV) in immunodeficient laboratory mice to develop a
mouse-adapted virus (maPgV) that established spontaneous persistent
life-long infection in a majority of normal lab mice. maRPgV viremia was
detected in the blood of mice for >300 days without apparent
disease, closely recapitulating the hallmarks of chronic HPgV infection in
humans. We found a pro-viral role for type-I interferon in chronic
infection; a lack of PD-1-mediated tolerance to PgV infection; and
multiple mechanisms by which PgV immunity can be achieved by an
immunocompetent host. These data indicate that the PgV immune evasion
strategy has aspects that are both common and unique among persistent
viral infections. The creation of maPgV represents the first PgV infection
model in wild-type mice, thus opening the entire toolkit of the mouse host
to enable further investigation of persistent RNA infections.