Inhibition of HIV-1 reactivation by a telomerase-derived peptide in a HSP90-dependent manner.

Hong Kim,Myung-Soo Choi,Kyung-Soo Inn,Bum-Joon Kim

doi:10.1038/srep28896

Hong Kim, Myung-Soo Choi + Show 2 more

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https://doi.org/10.1038/srep28896

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Abstract

A peptide vaccine designed to induce T-cell immunity to telomerase, GV1001, has been shown to modulate cellular signaling pathways and confer a direct anti-cancer effect through the interaction with heat shock protein (HSP) 90 and 70. Here, we have found that GV1001 can modulate transactivation protein-mediated human immunodeficiency virus (HIV)-1 transactivation in an HSP90-dependent manner. GV1001 treatment resulted in significant suppression of HIV-1 replication and rescue of infected cells from death by HIV-1. Transactivation of HIV-long terminal repeat (LTR) was inhibited by GV1001, indicating that GV1001 suppressed the transcription from proviral HIV DNA. The anti-HIV-1 activity of GV1001 was completely abrogated by an HSP90-neutralizing antibody, indicating that the antiviral activity depends on HSP90. Further mechanistic studies revealed that GV1001 suppresses basal NF-κB activation, which is required for HIV-1 LTR transactivation in an HSP90-dependent manner. Inhibition of LTR transactivation by GV1001 suggests its potential to suppress HIV-1 reactivation from latency. Indeed, PMA-mediated reactivation of HIV-1 from latent infected cells was suppressed by GV1001. The results suggest the potential therapeutic use of GV1001, a peptide proven to be safe for human use, as an anti-HIV-1 agent to suppress the reactivation from latently infected cells.

Highlights

Human reverse transcriptase subunit of telomerase is highly expressed in various cancer tissues and it has been considered as an attractive target for the development of effective cancer vaccines[1]
We have shown that GV1001 interacts with extracellular heat shock protein 90 (HSP90) and penetrates into the cytoplasm of cells[8]
Considering that GV1001 interacts with HSP90 and modulates cell signaling, we explored the possible antiviral role of GV1001 against human immunodeficiency virus (HIV)-1 in the current study

Summary

Introduction

Human reverse transcriptase subunit of telomerase (hTERT) is highly expressed in various cancer tissues and it has been considered as an attractive target for the development of effective cancer vaccines[1]. GV1001 exerted a strong anti-cancer effect through the interaction with HSP90 under hypoxic conditions by modulating the HIF-1α-VEGF signaling axis[9]. These studies indicate that GV1001 can regulate intracellular signaling pathways through the interaction with HSP90. EHSP90 plays distinct functions from those of intracellular HSP90, and it can regulate cell signaling pathways by interacting with various cell surface proteins[17]. Robust production of viral proteins requires HSP functions, and the list of viruses suppressed by HSP90 inhibitors continues to grow[19]. Considering that GV1001 interacts with HSP90 and modulates cell signaling, we explored the possible antiviral role of GV1001 against HIV-1 in the current study

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