Compounds producing an effective combinatorial regimen for disruption of HIV-1 latency.

Abstract:

:Highly active antiretroviral therapy (HAART) has improved the outlook for the HIV epidemic, but does not provide a cure. The proposed "shock-and-kill" strategy is directed at inducing latent HIV reservoirs, which may then be purged via boosted immune response or targeting infected cells. We describe five novel compounds that are capable of reversing HIV latency without affecting the general T-cell activation state. The new compounds exhibit synergy for reactivation of latent provirus with other latency-reversing agents (LRAs), in particular ingenol-3-angelate/PEP005. One compound, designated PH02, was efficient at reactivating viral transcription in several cell lines bearing reporter HIV-1 at different integration sites. Furthermore, it was capable of reversing latency in resting CD4+ T lymphocytes from latently infected aviremic patient cells on HAART, while producing minimal cellular toxicity. The combination of PH02 and PEP005 produces a strong synergistic effect for reactivation, as demonstrated through a quantitative viral outgrowth assay (qVOA), on CD4+ T lymphocytes from HIV-1-infected individuals. We propose that the PH02/PEP005 combination may represent an effective novel treatment for abrogating persistent HIV-1 infection.

journal_name

EMBO Mol Med

journal_title

EMBO molecular medicine

authors

Hashemi P,Barreto K,Bernhard W,Lomness A,Honson N,Pfeifer TA,Harrigan PR,Sadowski I

doi

10.15252/emmm.201708193

subject

Has Abstract

pub_date

2018-02-01 00:00:00

pages

160-174

issue

2

eissn

1757-4676

issn

1757-4684

pii

emmm.201708193

journal_volume

10

pub_type

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