Introduction In vivo, the state of latency allows HIV-1 to persist in cellular reservoirs and avoid eradication. Intracellular heat shock protein 90 (Hsp90) was shown to contribute to HIV-1 reactivation from latency, so that cell-permeable inhibitors of the Hsp90 chaperone activity can prevent this reactivation and be considered as potential anti-AIDS agents. However, the Hsp90 activity inhibitors provoke up-regulation of inducible Hsp90, Hsp70, Hsp27 and we suggested that such accumulation of chaperones in cellular reservoirs assists the virus and impairs the beneficial effects of Hsp90-inhibiting treatment. Here we examined whether the suppressive action of Hsp90 inhibitors on the HIV-1 reactivation is enhanced by targeting the Hsp induction and/or the chaperone function of Hsp70.
Methods The HIV-1 reactivation was studied in cultured J-Lat cells. 17AAG and AUY922 were used as the Hsp90 activity inhibitors. The Hsp accumulation in the Hsp90 inhibitor-treated cells was blocked by co-treatments with quercetin or KNK437. The Hsp70 chaperone function was inhibited by 2-phenylethynesulfonamide (PES).
Results Inhibition of the Hsp90 chaperone activity with 17AAG or AUY922 does suppress the HIV-1 reactivation in the drug-treated cells but this is also accompanied by the up-regulation of Hsp90, Hsp70 and Hsp27. In the case of inhibitory co-treatments (17AAG or AUY922 + quercetin or KNK437 + PES), no increase in the cellular Hsp levels occurred despite of the dysfunction of Hsp90-,Hsp70-dependent chaperone machine. Such a combination of the inhibitors simultaneously targeting the chaperone activities of Hsp90 and Hsp70 and the Hsp induction much stronger suppressed the chaperone-dependent HIV-1 reactivation, as compared with the action of Hsp90 inhibitors alone.
Conclusion Intracellular Hsp70 appears to contribute to the HIV-1 reactivation from latency. The suppressive effects of Hsp90-inhibiting drugs on the HIV-1 reactivation from latency can be enhanced by parallel inhibiting both the Hsp induction and the Hsp70 chaperone activity.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.