Dendritic cell-specific hypoxia-inducible factor-1α deficiency protects mice from recurrent retroviral infection.

Antigen-processing and -presenting cells play a pivotal role in initiation of the antiviral immune response. The cellular adaption of dendritic cells to reduced oxygen and nutrition levels at the site of infection is regulated predominantly by the transcription factor complex hypoxia-inducible factor-1 (HIF-1). For a better understanding of the influence of dendritic HIF-1 on the outcome of a retroviral infection, we infected wild-type and CD11c-specific HIF-1α knockout mice with the murine Friend leukaemia virus (FV) to cause an acute to chronic infection. Chronic FV infection caused a much more severe clinical course in control mice than in knockout mice, although no gross differences in spleen weight and immune cell population during acute FV infection were observed. Following chronic FV infection, half of the control mice developed massive splenomegaly accompanied by a complete loss of splenic architecture, whereas the remaining control mice appeared able to control viral replication. In contrast, without exception all knockout mice were able to restrict viral replication. Furthermore, control mice showed increased numbers of antigen-presenting cells with impaired activation and decreased adaptive immune response. Given that our knockout construct leads to an HIF-1α protein without a functional DNA binding domain, and it was already shown that HIF-1α plays a non-transcriptional role in DNA replication, we analysed basal HIF-1α mRNA expression. All animals with a very low basal HIF-1α expression incurred FV recurrence, whereas higher basal expression was protective against recurrence. These results might indicate a novel role of HIF-1α in control of chronic viral infections.