NF-κB sub-pathways and HIV cure: A revisit

Abstract

HIV cure is thwarted by the presence of quiescent yet replication competent HIV-1 (HIV). Antiretroviral therapy (ART) is unable to eradicate reservoirs, and upon cessation of ART, HIV will rebound. This review encompasses the curative strategies of HIV in the context of NF-κB sub-pathways that are currently exploited and demonstrate promise in the disruption of latent HIV. Canonical NF-κB signaling has long been established to drive HIV proviral expression while noncanonical NF-κB signaling, a novel and perhaps more desirable mechanism of latency reversal due to its unique characteristics, has recently been shown to also promote HIV expression from latency. Furthermore, we discuss the previously unrecognized upstream signaling of NF-κB as a new avenue for exploration of a functional cure of HIV.

Voacanga globosa Spirobisindole Alkaloids Exert Antiviral Activity in HIV Latently Infected Cell Lines by Targeting the NF-κB Cascade: In Vitro and In Silico Investigations

“…Insufficient expression and inactivity of these factors block successful replication and are related to latency shift [ 9 , 11 , 12 ]. In addition, NF-κB is widely established in HIV latently infected cells and functions in the early phase of HIV transcription, therefore emerging as a target of anti-HIV chemotherapy [ 14 , 15 ]. Moreover, upstream signaling proteins that eventually activate NF-κB are targeted by pharmacological compounds such as bryologs, phorbol esters, and alkaloids [ 15 , 16 , 17 ].…”

Crotonylation sensitizes IAPi-induced disruption of latent HIV by enhancing p100 cleavage into p52

“…This was possibly controlled by TRIM27 ubiquitination signaling pathway at the step of p100 cleavage into p52, in addition to the epigenetic regulation of HIV transcription at the HIV LTR ( Jiang et al., 2018 ). These findings provide a deep understanding of the complexity of NF-κB signaling during HIV transcription and the establishment of HIV latency ( Wong and Jiang, 2021 ; Yang et al., 2020 ), which will help us design alternative tools to deplete stable HIV reservoirs in future.…”

“…In addition to the canonical NF-κB (cNF-κB) pathway, other NF-κB subpathways regulate gene transcription via NF-κB DNA binding sites ( Wong and Jiang, 2021 ). These include noncanonical NF-κB (ncNF-κB) and atypical NF-κB pathways ( Sun, 2012 ; Sun and Ley, 2008 ; Wong and Jiang, 2021 ).…”

“…In addition to the canonical NF-κB (cNF-κB) pathway, other NF-κB subpathways regulate gene transcription via NF-κB DNA binding sites ( Wong and Jiang, 2021 ). These include noncanonical NF-κB (ncNF-κB) and atypical NF-κB pathways ( Sun, 2012 ; Sun and Ley, 2008 ; Wong and Jiang, 2021 ). For example, whereas RelA/p50 is released from IκB after IκB phosphorylation and ubiquitination during canonical NF-kB signaling, the activation of ncNF-κB is dependent on the cleavage of p100 into p52 after p100 phosphorylation by NF-κB activating kinase (NIK) ( Sun, 2012 ).…”

The Current Status of Latency Reversing Agents for HIV-1 Remission

“…Importantly, Yukl et al (153) demonstrated that the different classes of LRAs are not able to reverse all the post-transcriptional blocks but rather are specific to one or two post-transcriptional mechanisms, thereby reinforcing the use of combinatory treatment to reverse all post-transcriptional blocks repressing HIV-1 gene expression and to fully reactivate the viral reservoirs. Finally, regarding the use of SMAC mimetics, their combination with other LRAs will probably be assessed in the near future, as discussed by the Jiang group (155).…”