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Originally published online as doi:10.1189/jlb.0506361 on October 24, 2006

Published online before print October 24, 2006
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(Journal of Leukocyte Biology. 2007;81:528-538.)
© 2007 by Society for Leukocyte Biology

Hypoxia inhibits Moloney murine leukemia virus expression in activated macrophages

Maura Puppo*,1, Maria Carla Bosco*,1, Maurizio Federico{dagger}, Sandra Pastorino*,2 and Luigi Varesio*,3

* Laboratory of Molecular Biology, G. Gaslini Institute, Genova, Italy; and
{dagger} National AIDS Center, Division of Pathogenesis of Retrovirus, Istituto Superiore di Sanità, Rome, Italy

3 Correspondence: Laboratorio di Biologia Molecolare, Istituto Giannina Gaslini, Padiglione 2, L.go Gerolamo Gaslini 5, 16147 Genova Quarto, Italy. E-mail: luigivaresio{at}ospedale-gaslini.ge.it

Hypoxia, a local decrease in oxygen tension, occurring in many pathological processes, modifies macrophage (M{phi}) 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-{gamma}-activated M{phi}. 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 M{phi} 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 M{phi} lineage-selective action. Finally, we found that MoMLV-mediated gene expression in M{phi} was also inhibited by picolinic acid, a tryptophan catabolite with hypoxia-like activity and M{phi}-activating properties, suggesting a pathophysiological role of this molecule in viral resistance and its possible use as an antiviral agent.

Key Words: monocytes • retrovirus • gene regulation




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F. Battaglia, S. Delfino, E. Merello, M. Puppo, R. Piva, L. Varesio, and M. C. Bosco
Hypoxia transcriptionally induces macrophage-inflammatory protein-3{alpha}/CCL-20 in primary human mononuclear phagocytes through nuclear factor (NF)-{kappa}B
J. Leukoc. Biol., March 1, 2008; 83(3): 648 - 662.
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