Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication

Abstract

BackgroundExisting highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy that is being actively pursued to eliminate the latent aspect of HIV-1 infection involves therapies combining latency antagonists with HAART. However, discordant pharmacokinetics between these types of drugs can potentially create sites of active viral replication within certain tissues that might be impervious to HAART.ResultsA preliminary reverse genetic screen indicated that the proteasome might be involved in the maintenance of the latent state. This prompted testing to determine the effects of proteasome inhibitors (PIs) on latently infected cells. Experiments demonstrated that PIs effectively activated latent HIV-1 in several model systems, including primary T cell models, thereby defining PIs as a new class of HIV-1 latency antagonists. Expanding upon experiments from previous reports, it was also confirmed that PIs inhibit viral replication. Moreover, it was possible to show that PIs act as bifunctional antagonists of HIV-1. The data indicate that PIs activate latent provirus and subsequently decrease viral titers and promote the production of defective virions from activated cells.ConclusionsThese results represent a proof-of-concept that bifunctional antagonists of HIV-1 can be developed and have the capacity to ensure precise tissue overlap of anti-latency and anti-replication functions, which is of significant importance in the consideration of future drug therapies aimed at viral clearance.

Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition

“…1A shows that both BTZ and MG-132 effectively induced latent HIV LTR-driven expression of GFP. This is in agreement with a previous report (6). In addition, we found that CFZ exerted a similar activity as BTZ did.…”

“…In comparison, CD69, TNF-␣, IL-2, and IL-17␣ were up-regulated under the treatment with prostratin in addition to IL-1␤ and IL-18. Because the transcription of genes closely related to HIV infection are inhibited, it could provide further evidence that PIs are bifunctional HIV antagonists as previously described (6). The decrease in inflammatory cytokines might imply an anti-inflammatory effect of PIs.…”

“…Unexpectedly, bortezomib (BTZ) was reported as a bifunctional HIV antagonist. It inhibits HIV infection and also reactivates latent HIV with reduced infectivity (6). However, the mechanism of latent HIV reactivation via PIs remains to be elucidated.…”

Differential expression of lncRNAs during the HIV replication cycle: an underestimated layer in the HIV-host interplay

“…Indeed, it has been shown that (immuno-) proteasomes are recruited for cellular defense against incoming pathogens (i.e. HIV)484950. These complexes digest viral proteins and provide small peptides that can be presented by Major Histocompatibility Complex I (MHC-I) molecules on the cell surface in order to be recognized and killed by other immune cells.…”

Challenges and strategies for the eradication of the HIV reservoir

“…This selective reactivation is an enormous challenge given that the Poll II transcriptional apparatus, which transcribes the HIV provirus, also transcribes all cellular protein coding genes. LRAs with ability to reactive HIV include histone deacetylase inhibitors (HDACi) [34,35], histone methyltransferase inhibitors [36], the anti-alcoholism drug disulfiram [37], protein kinase C (PKC) agonists [38-40], proteasome inhibitors [41], and Toll-like receptor 7 (TLR-7) agonist [42]. Of these LRAs, the PKC agonist, Ingenol 3,20-dibenzoate, and a TLR-7 agonist, have demonstrated the most significant effects on reactivation of HIV and SIV, respectively.…”