Abstract
Adaptive immune responses to primary Kaposi sarcoma-associated herpesvirus (KSHV) infection are poorly defined. To develop better small-animal models for understanding KSHV pathogenesis and immunity, we previously generated a chimeric virus in which the KSHV latency-associated nuclear antigen (kLANA), a conserved multifunctional protein critical for viral latency, was exchanged for the LANA homolog in murine gammaherpesvirus 68 (MHV68). Despite comparable levels of latent infection between WT and KLKI MHV68, kLANA directly repressed MHV68 lytic replication and reactivation. We therefore hypothesized that suppression of lytic replication by kLANA dampens adaptive immune responses. To test this, mice were infected with equivalent doses of either WT or KLKI MHV68 and adaptive immune responses were evaluated over time. B and T cell activation was starkly reduced following KLKI MHV68 infection, despite a potent virus-specific effector CD8+ T cell response against both viruses. These phenotypes were independent of inoculating dose, as high dose infection with KLKI MHV68 still showed reduced adaptive immune cell activation. In contrast, infection of Ifnar1(-/-) mice, which support enhanced KLKI MHV68 lytic replication, led to potent adaptive cellular and humoral immune activation by both WT and KLKI viruses, suggesting that the level of viral replication, and not simply amount of virus present, is a major driver of adaptive immunity during GHV infection. Collectively, these data support the hypothesis that kLANA-mediated suppression of lytic replication facilitates immune evasion by holding viral replication below a threshold for potent induction of adaptive immunity.