Date Published: February 4, 2019
Publisher: Public Library of Science
Author(s): Michael Bobardt, Joseph Kuo, Udayan Chatterji, Sumit Chanda, Susan J. Little, Norbert Wiedemann, Gregoire Vuagniaux, Philippe A. Gallay, Nicolas Sluis-Cremer.
Antiretroviral therapy (ART) suppresses HIV replication, but does not cure the infection because replication-competent virus persists within latently infected CD4+ T cells throughout years of therapy. These reservoirs contain integrated HIV-1 genomes and can resupply active virus. Thus, the development of strategies to eliminate the reservoir of latently infected cells is a research priority of global significance. In this study, we tested efficacy of a new inhibitor of apoptosis protein antagonist (IAPa) called Debio 1143 at reversing HIV latency and investigated its mechanisms of action. Debio 1143 activates HIV transcription via NF-kB signaling by degrading the ubiquitin ligase baculoviral IAP repeat-containing 2 (BIRC2), a repressor of the non-canonical NF-kB pathway. Debio 1143-induced BIRC2 degradation results in the accumulation of NF-κB-inducing kinase (NIK) and proteolytic cleavage of p100 into p52, leading to nuclear translocation of p52 and RELB. Debio 1143 greatly enhances the binding of RELB to the HIV-1 LTR. These data indicate that Debio 1143 activates the non-canonical NF-kB signaling pathway by promoting the binding of RELB:p52 complexes to the HIV-1 LTR, resulting in the activation of the LTR-dependent HIV-1 transcription. Importantly, Debio 1143 reverses viral latency in HIV-1 latent T cell lines. Using knockdown (siRNA BIRC2), knockout (CRIPSR NIK) and proteasome machinery neutralization (MG132) approaches, we found that Debio 1143-mediated HIV latency reversal is BIRC2 degradation- and NIK stabilization-dependent. Debio 1143 also reverses HIV-1 latency in resting CD4+ T cells derived from ART-treated patients or HIV-1-infected humanized mice under ART. Interestingly, daily oral administration of Debio 1143 in cancer patients at well-tolerated doses elicited BIRC2 target engagement in PBMCs and induced a moderate increase in cytokines and chemokines mechanistically related to NF-kB signaling. In conclusion, we provide strong evidences that the IAPa Debio 1143, by initially activating the non-canonical NF-kB signaling and subsequently reactivating HIV-1 transcription, represents a new attractive viral latency reversal agent (LRA).
According to estimates by WHO and UNAIDS, approximately 40 million people are currently living with HIV-1. According to the latest estimates from the Centers for Disease Control and Prevention, 38,500 people became newly infected with HIV-1 in the United States in 2015, and 2.1 million worldwide . Antiretroviral therapy (ART) represses HIV-1 replication and stops disease progression, allowing infected people to live with the infection . Yet, ART does not eliminate the infection since replication-competent HIV-1 survives in latently infected CD4+ T cells during many years of ART [3–5]. Resting CD4+ T cells harbor integrated viral genomes and serve as permanent source of de novo infectious viruses. Long-term ART is accompanied with issues including health problems due to chronic drug exposure, expensive cost and stringent compliance requirement . Thus, new strategies to eradicate these viral reservoirs represent an utmost clinical priority.