The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate

Abstract

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).

The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice

“…As previously reported [50,55], the anti-PD-1 mAb treatment profoundly reduced blood HIV-1 loads (Fig 3B) compared to the vehicle treatment ( Fig 3A). D1143 treatment enhanced blood HIV load compared to the vehicle treatment ( Fig 3C) likely by enhancing viral transcription as we described previously [36]. D1143 amplified the anti-PD-1 mAb-mediated suppression of blood HIV loads at week 13, 14 and 15 ( Fig 3D) although the D1143 enhancement of the anti-PD-1 treatment was not statistically significant ( Fig 3F).…”

“…Our previous finding that D1143 reverses HIV latency by modulating the non-canonical NF-kB response [36], and our present finding that D1143 enhances PD-1 blockade effects on CD8+ T cells represent attractive properties for testing the combination of D1143 and anti-PD-1 mAb in a HIV latency model. Therefore, a similar study will be conducted in HIVinfected humanized mice under ART.…”

“…IAPa binding modulates the ubiquitin ligase function of these IAP members [33][34][35]. We recently reported that the IAPa D1143 modulates the non-canonical NF-kB pathway by rapidly degrading a repressor of this important signaling pathway-the baculoviral IAP repeat-containing 2 (BIRC2) [36].…”

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

“…The ability of pro-apoptotic molecules to induce NF-κB pathways and reactivate HIV-1 latency is not without precedence. Second mitochondria-derived activator of caspase (SMAC) mimetics such as LCL-161, SBI-0637142, birinipant, Debio1143 and AZD5582 that target the host antiapoptotic factors XIAP and cIAP1/BIRC2 have been demonstrated to be potent LRAs via the activation of the non-canonical NF-κB pathways [54][55][56] . Some LRAs have also been demonstrated to promote cell death, as seen with benzolactam derivatives that are PKC agonists and induce apoptosis in latent HIV-1-infected cells 57,58 .…”

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

“…Among the SMAC mimetics tested thus far, SBI-0637142 and LCL161 are able to downregulate BIRC2, leading to proviral transcription [111]. Interestingly, the SMAC mimetic SBI-0637142 produces synergistic induction of HIV expression when combined with HDAC inhibitors, and induces apoptosis within latently infected CD4+ T cells where viral replication has been reactivated [112]. Three different SMAC mimetics including birinapant, GDC-0152, and a benzolactam-related compound, BL-V8-310, were shown to induce this selective cell death within HIV-1 infected central memory CD4 T cells [113].…”