Thiostrepton reactivates latent HIV-1 through p-TEFb and NF- κB pathway mediated by heat shock response.

Thiostrepton reactivates latent HIV-1 through p-TEFb and NF-κB pathway mediated by heat shock response. Antimicrob Agents Chemother. 2020 Feb 24;: Authors: Peng W, Hong Z, Chen X, Gao H, Dai Z, Zhao J, Liu W, Li D, Deng K Abstract Antiretroviral therapy (ART) suppresses HIV-1 replication, but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4+ T cells, remains a major obstacle to viral eradication. "Shock and Kill" strategy targets these latently-infected cells and boosts immune recognition and clearance, which continues to be a promising approach for HIV-1 functional cure. Although some latency reversing agents (LRAs) have been reported, no apparent clinical progress has been made, so it is still vitally important to seek for novel and effective LRAs. Here we report that thiostrepton (TSR), a proteasome inhibitor, reactivates latent HIV-1 effectively in cellular models and in primary CD4+ T cells from ART-suppressed individuals ex vivo TSR does not induce global T cell activation, severe cytotoxicity or CD8+ T cell dysfunction, making it a prospective LRA candidate. We also observed a significant synergistic effect of reactivation when combining TSR with JQ1, prostratin or bryostatin-1. Interestingly, 6 TSR analogues also show similar or more effective reactivation abilities comparing to TSR. We further verified that TSR upregulated expression of heat shock prote...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research