Cellular adaption to hypoxia is controlled by the transcription factor complex hypoxia-inducible factor (HIF)-1. In addition, HIF-1 regulates the gene expression profile of dendritic cells and macrophages during inflammation. HIF-1 is composed of a constitutive HIF-1β subunit and an oxygen/inflammation controlled HIF-1α subunit. To investigate the role of HIF-1 in viral infections we infected control mice which show activation of HIF-1α and mice with a dendritic cell specific HIF-1α knockout with the murine Friend leukemia virus. Friend virus infection caused a much severer infection in control than in knockout mice. Control mice exhibited a more pronounced splenomegaly accompanied by an almost complete loss of germinal centers in the spleen. Additionally, these mice showed a decreased adaptive immune response and increased numbers of dendritic cells and granulocytes after chronic infection. Ex vivo cultured bone marrow-derived dendritic cells showed an increased induction of HIF-1α protein after acute and chronic infection. Thus, we propose that viral infection increases dendritic HIF-1α which has an important influence on the course of chronic Friend virus infection. HIF-1α deficiency in dendritic cells apparently leads to a better recovery after long-term viral infection.