HIV-1 protease inhibitors do not interfere with provirus transcription and host cell apoptosis induced by combined treatment TNF-alpha + TSA

Abstract

HIV-1 latency represents a major hurdle to the complete eradication of the virus from patients under highly active anti-retroviral therapy (HAART) regimens. One solution to this problem would be to eliminate the latently infected cellular reservoirs by forcing gene expression in presence of HAART to prevent spreading of the infection by the newly synthesized viruses. Many studies have reported that a combination of a histone deacetylase inhibitor (HDACi) (i.e. TSA, NaBut, Valproic acid, ...) with a pro-inflammatory cytokine (i.e. TNFalpha, IL-1, ...) reactivates in a synergistic manner HIV-1 transcription in latently infected cells. The aim of the present study was to determine whether HIV-1 protease inhibitors (PIs) used in HAART (such as Saquinavir, Indinavir, Nelfinavir, Lopinavir, Ritonavir and Amprenavir) could interfere with the potential purge of the cellular reservoirs induced by a combined treatment involving TSA and TNFalpha. We showed, in two HIV-1 latently infected cell lines (ACH-2 and U1) that all PIs efficiently inhibited release of mature viral particles but did neither affect cell apoptosis nor NF-kappaB induction and HIV-1 transcription activation following combined treatment with TNFalpha+TSA. This study is encouraging in the fight against HIV-1 and shows that PIs should be compatible with an inductive adjuvent therapy for latent reservoir reduction/elimination in association with efficient HAART regimens.