Abstract
The persistence of HIV in resting memory CD4+ T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex. Specifically, HSP90 downstream HSF1 gives positive feedback to the reactivation process through binding to cyclin-dependent kinase 9 (CDK9) and preventing it from undergoing degradation by the proteasome. Overall, these findings suggest proteasome inhibitors as potential latency reversing agents. In addition, HSF1/HSP90 involved in HIV transcription elongation, may serve as therapeutic targets in HIV eradication.
Highlights
The persistence of HIV in resting memory CD4؉ T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV
We found that heat shock factor 1 (HSF1) was activated and it recruited the HSP901⁄7p-TEFb complex to promote transcription elongation
Besides HSF1, cyclin-dependent kinase 9 (CDK9) was found to accumulate in the nucleus (Fig. 4A). This result indicates that transcription elongation in relationship to positive transcriptional elongation factor b (p-TEFb) might widely participate in latent HIV reactivation induced by proteasome inhibition
Summary
The persistence of HIV in resting memory CD4؉ T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. HSP90 downstream HSF1 gives positive feedback to the reactivation process through binding to cyclin-dependent kinase 9 (CDK9) and preventing it from undergoing degradation by the proteasome. Overall, these findings suggest proteasome inhibitors as potential latency reversing agents. Joshi et al [12] reported that inhibition of HSP90 prevents the recovery of HIV This suggests HSP90 inhibitors as alternatives or supplementary to cART to suppress the formation of persistent HIV reservoirs [12]. These studies confirm a role for HSP90 in latent HIV reactivation. Besides shedding light on the mechanism of PIs reactivation of latent HIV, this study suggests HSF1/HSP90 as potential therapeutic targets
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