Immune determinants of pegivirus persistence, control, and cross-species infection in the laboratory mouse

Approximately 15% of the global human population is viremic with human pegivirus (HPgV), a +ssRNA virus in the Flaviviridae family. An unusual feature of HPgV is its ability to persistently infect individuals without causing overt disease or evoking robust immune responses, but this phenomenon is poorly understood due to a dearth of systems for studying HPgV. In this study, we create the first mouse model of PgV infection by adapting a PgV discovered in a wild rat (RPgV) to infect the standard laboratory mouse. Adaptation to the mouse initially required defective innate immunity and the accumulation of a single mutation in the E2 envelope glycoprotein, but passage into wild-type (WT) mice resulted in twelve additional mutations that enable persistent high-titer viremia, closely recapitulating the course of HPgV in humans. Mouse-adapted (ma)PgV infection of various knockout mice showed that lymphocytes exert a significant antiviral effect in the chronic phase of infection, but that this effect is also unable to fully control viremia in most individuals. Chronic type-I interferon signaling appears to paradoxically enable maPgV persistence, likely via T cell dysfunction that has been demonstrated in other chronic viral infections. However, unlike many persistent viruses, maPgV does not depend upon the induction of PD-1-mediated immune tolerance to maintain persistence. In-depth analysis of rare WT mice that achieved sterilizing maPgV immunity suggests that multiple possible paths to achieving PgV immunity exist and may include a combination of cellular, humoral, and non-canonical mechanisms. Altogether, our creation of maPgV opens up the vast murine toolkit for understanding the enigmatic biology of PgVs. In addition to novel insights into multiple aspects of PgV immunity, the lack of PD-1-mediated immune tolerance induced by PgV infection is unique among persistent viruses and suggests a highly novel mechanism of immune evasion. ### Competing Interest Statement The authors have declared no competing interest.