Increased gammaretrovirus integration following mifepristone administration

[natasa778]

Gene Ther. 2010 May 20. [Epub ahead of print]
Mifepristone increases gamma-retroviral infection efficiency by enhancing the integration of virus into the genome of infected cells.

Solodushko V, Fouty B.

[1] Center for Lung Biology, University of South Alabama School of Medicine, Mobile, AL, USA [2] Department of Pharmacology, University of South Alabama School of Medicine, Mobile, AL, USA.
Abstract

Gamma-retroviruses are commonly used to deliver genes to cells. Previously, we demonstrated that the synthetic anti-glucocorticoid and anti-progestin agent, mifepristone, increased gamma-retroviral infection efficiency in different target cells, independent of viral titer. In this study, we examine how this occurs. We studied the effect of mifepristone on different steps of viral infection (viral entry, viral survival, viral DNA synthesis and retrovirus integration into the host genome) in three distinct retroviral backbones using different virus recognition receptors. We also tested the potential role of glucocorticoid and progesterone receptors in mediating mifepristone's ability to increase gamma-retroviral infectivity. We show that mifepristone increases gamma-retroviral infection efficiency by facilitating viral integration into the host genome and that this effect seems to be due to mifepristone's anti-glucocorticoid, but not its anti-progestin, activity. These results suggest that inhibition of the glucocorticoid receptor enhances retroviral integration into the host genome and indicates that cells may have a natural protection again retroviral infection that may be reduced by glucocorticoid receptor antagonists.Gene Therapy advance online publication, 20 May 2010; doi:10.1038/gt.2010.80.

PMID: 20485384

 

[guest]

Thanks for posting it. I thought that glucocorticoids enhance the virus?

 

[lansbergen]

Thanks for posting it. I thought that glucocorticoids enhance the virus?

I thought corticoids activate the provirus.

If I understand it correctly now it seems an antagonist enhances intregration of the provirus.

I think both can be true. After intregration the antagonist has done its job.

The binding might be reversible and then cortisol can bind to the receptor and activate the intergrated provirus.

Mifepristone relative binding affinity at the glucocorticoid receptor is more than three times that of dexamethasone and more than ten times that of cortisol.

Everybody feel free to correct me.


http://en.wikipedia.org/wiki/Receptor_antagonist

Receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses.[1] In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to allosteric sites on receptors, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally-defined binding sites on receptors.