Gammaherpesvirus infection unveils exaggerated germinal center responses in an SR-BI-deficient host

Lipid metabolism has emerged as an important regulator of acute viral infections by affecting viral replication and the host immune response. In contrast, the role of host lipid metabolism during chronic viral infection has been less explored. The current study aims to define the role of scavenger receptor class B type I (SR-BI), a primary physiologic receptor for high-density lipoprotein (HDL), during natural gammaherpesvirus infection. Gammaherpesviruses are highly prevalent cancer-associated pathogens that induce and manipulate germinal center responses to establish life-long infection of B cells. Importantly, gammaherpesvirus-infected germinal center B cells are thought to be the target of viral transformation. In this study, we found that global SR-BI deficiency led to increased gammaherpesvirus lytic gene expression in the lungs during the acute stage of infection. Chronic gammaherpesvirus infection of the SR-BI-deficient host was associated with exaggerated germinal center responses and increased differentiation of self-reactive B cells that persisted during the long-term stage of chronic infection. Interestingly, SR-BI-deficient germinal center B cells, although more numerous, failed to support efficient gammaherpesvirus infection. The exaggerated germinal center response was also observed following immunization of the SR-BI-deficient host, unveiling the novel role of SR-BI as a negative regulator of physiological and gammaherpesvirus-driven germinal center responses.

Lipid metabolism affects diverse acute viral infections. In contrast, less is known about the effect of lipid metabolism on chronic virus infection, including in the context of an intact host. Host lipid homeostasis is maintained via a combination of endogenous lipid synthesis that takes place in most cell types and cellular interaction with exogenous, circulating lipids. This study focuses on defining the interaction between SR-BI, a primary HDL receptor, and natural gammaherpesvirus infection. We found that SR-BI deficiency led to increased expression of lytic gammaherpesvirus genes during acute gammaherpesvirus replication in the lungs. Importantly, chronic gammaherpesvirus infection unveiled the physiological role of SR-BI as a negative regulator of the germinal center response, a B cell differentiation process that is critical for physiological B cell responses and that is manipulated by gammaherpesviruses to establish chronic infection.