P5.16 Combination of inhibitors of chaperone activity and chaperone expression for prevention of hiv-1 reactivation from latency

Abstract

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.