Open AccessCompounds producing an effective combinatorial regimen for disruption of HIV ‐1 latency
Author(s) -
Hashemi Pargol,
Barreto Kris,
Bernhard Wendy,
Lomness Adam,
Honson Nicolette,
Pfeifer Tom A,
Harrigan P Richard,
Sadowski Ivan
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708193
Subject(s) - latency (audio) , human immunodeficiency virus (hiv) , chemistry , lentivirus , virology , computer science , biology , viral disease , telecommunications
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 ( LRA s), in particular ingenol‐3‐angelate/ PEP 005. One compound, designated PH 02, 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 CD 4 + T lymphocytes from latently infected aviremic patient cells on HAART , while producing minimal cellular toxicity. The combination of PH 02 and PEP 005 produces a strong synergistic effect for reactivation, as demonstrated through a quantitative viral outgrowth assay ( qVOA ), on CD 4 + T lymphocytes from HIV ‐1‐infected individuals. We propose that the PH 02/ PEP 005 combination may represent an effective novel treatment for abrogating persistent HIV ‐1 infection.