Pivotal pathways that control host responses to lentivirus infection. (VIR7P.1053)

Abstract

Abstract Lentiviruses such as Human Immunodeficiency Virus establish persistent infections but it is unclear how lentiviruses evade host immunity. To elucidate pivotal pathways driving tolerogenic host responses to lentiviral infection we used the murine leukemia virus (LP-BM5) infection model, which causes persistent infections leading to splenomegaly, immunosuppression, and increased risk of leukemia. LP-BM5 infection induced indoleamine 2,3 dioxygenase (IDO) enzyme activity in a subset of dendritic cells expressing the B cell marker CD19 that regulate T cells. Different mouse strains exhibit variable resistance to LP-BM5 infection but all mice succumb to persistent LP-BM5 infection. In contrast, mice with genetically-induced, functional defects in Foxp3-lineage regulatory CD4 T cells (Tregs) cleared LP-BM5 infections ~4-6 weeks post infection. LP-BM5 clearance did not occur unless mice were homozygous for defective Foxp3 alleles, indicating that wild-type Tregs mediate dominant tolerogenic responses to LP-BM5 infection. Depleting CD8 T cells prevented LP-BM5 clearance in Treg defective mice, and LP-BM5 resistance correlated with diminished IDO induction, suggesting that Tregs block CD8 T cells via IDO to promote virus persistence. Thus Tregs are pivotal in promoting tolerogenic responses to LP-BM5 infection, and interfering with pathways that activate Tregs and mediate responses to activated Tregs may enhance host resistance to lentivirus infections.