Combination antiretroviral therapy (ART) is able to suppress HIV-1 replication to undetectable levels. However, the persistence of latent viral reservoirs allows for a rebound of viral load upon cessation of therapy. Thus, therapeutic strategies to eradicate the viral latent reservoir are critically needed. Employing a targeted RNAi screen, we identified the ubiquitin ligase BIRC2 (cIAP1), a repressor of the noncanonical NF-κB pathway, as a potent negative regulator of LTR-dependent HIV-1 transcription. Depletion of BIRC2 through treatment with small molecule antagonists known as Smac mimetics enhanced HIV-1 transcription, leading to a reversal of latency in a JLat latency model system. Critically, treatment of resting CD4+ T cells isolated from ART-suppressed patients with the histone deacetylase inhibitor (HDACi) panobinostat together with Smac mimetics resulted in synergistic activation of the latent reservoir. These data implicate Smac mimetics as useful agents for shock-and-kill strategies to eliminate the latent HIV reservoir.

BIRC2/cIAP1 is a Negative Regulator of HIV-1 Transcription and Can Be Targeted by Smac Mimetics to Promote Reversal of Viral Latency / L. Pache, M.S. Dutra, A.M. Spivak, J.M. Marlett, J.P. Murry, Y. Hwang, A.M. Maestre, L. Manganaro, M. Vamos, P. Teriete, L.J. Martins, R. Konig, V. Simon, A. Bosque, A. Fernandez-Sesma, N.D.P. Cosford, F.D. Bushman, J.A.T. Young, V. Planelles, S.K. Chanda. - In: CELL HOST & MICROBE. - ISSN 1931-3128. - 18:3(2015), pp. 345-353. [10.1016/j.chom.2015.08.009]

BIRC2/cIAP1 is a Negative Regulator of HIV-1 Transcription and Can Be Targeted by Smac Mimetics to Promote Reversal of Viral Latency

L. Manganaro;
2015

Abstract

Combination antiretroviral therapy (ART) is able to suppress HIV-1 replication to undetectable levels. However, the persistence of latent viral reservoirs allows for a rebound of viral load upon cessation of therapy. Thus, therapeutic strategies to eradicate the viral latent reservoir are critically needed. Employing a targeted RNAi screen, we identified the ubiquitin ligase BIRC2 (cIAP1), a repressor of the noncanonical NF-κB pathway, as a potent negative regulator of LTR-dependent HIV-1 transcription. Depletion of BIRC2 through treatment with small molecule antagonists known as Smac mimetics enhanced HIV-1 transcription, leading to a reversal of latency in a JLat latency model system. Critically, treatment of resting CD4+ T cells isolated from ART-suppressed patients with the histone deacetylase inhibitor (HDACi) panobinostat together with Smac mimetics resulted in synergistic activation of the latent reservoir. These data implicate Smac mimetics as useful agents for shock-and-kill strategies to eliminate the latent HIV reservoir.
CD4-Positive T-Lymphocytes; Cells, Cultured; HIV-1; Humans; Hydroxamic Acids; Indoles; Inhibitor of Apoptosis Proteins; Oligopeptides; Panobinostat; Transcription, Genetic; Ubiquitin-Protein Ligases; Virus Activation; Virus Latency; Gene Expression Regulation, Viral; Host-Pathogen Interactions
Settore BIO/19 - Microbiologia Generale
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/886487
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