Hypoxia inhibits Moloney murine leukemia virus expression in activated macrophages

Hypoxia, a local decrease in oxygen tension, occurring in many pathological processes, modifies macrophage (Mφ) gene expression and function. Here, we provide the first evidence that hypoxia inhibits transgene expression driven by the Moloney murine leukemia virus‐long terminal repeats (MoMLV‐LTR) in IFN‐γ‐activated Mφ. Hypoxia silenced the expression of several MoMLV‐LTR‐driven genes, including v‐myc , enhanced green fluorescence protein, and env , and was effective in different mouse Mφ cell lines and on distinct MoMLV backbone‐based viruses. Down‐regulation of MoMLV mRNA occurred at the transcriptional level and was associated with decreased retrovirus production, as determined by titration experiments, suggesting that hypoxia may control MoMLV retroviral spread through the suppression of LTR activity. In contrast, genes driven by the CMV or the SV40 promoter were up‐regulated or unchanged by hypoxia, indicating a selective inhibitory activity on the MoMLV promoter. It is interesting that hypoxia was ineffective in suppressing MoMLV‐LTR‐controlled gene expression in T or fibroblast cell lines, suggesting a Mφ lineage‐selective action. Finally, we found that MoMLV‐mediated gene expression in Mφ was also inhibited by picolinic acid, a tryptophan catabolite with hypoxia‐like activity and Mφ‐activating properties, suggesting a pathophysiological role of this molecule in viral resistance and its possible use as an antiviral agent.