Targeting NF-κB Signaling for HIV Latency Reversal: Mechanisms, Challenges, and Therapeutic Perspectives

HIV latency remains a major barrier to achieving a definitive cure, as replication-competent proviruses persist in resting CD4⁺ T cells despite prolonged antiretroviral therapy (ART). The nuclear factor kappa B (NF-κB) signaling pathway plays a central role in both latency maintenance and viral reactivation through its regulation of HIV transcription. In resting T cells, low NF-κB activity promotes a repressive chromatin state at the viral long terminal repeat (LTR), whereas activation of canonical or non-canonical NF-κB signaling can initiate transcription and reactivate latent HIV. Pharmacological targeting of NF-κB, including protein kinase C (PKC) agonists, second mitochondria-derived activator of caspase (SMAC) mimetics, and combinations with histone deacetylase inhibitors, has shown potential as latency-reversing strategies within the "shock-and-kill" framework. However, global NF-κB activation is associated with systemic inflammation, off-target gene induction, and limited clinical efficacy of many latency-reversing agents (LRAs). Emerging approaches therefore emphasize selective modulation of NF-κB signaling using precision small molecules, immunotherapeutic combinations, and RNA-based regulators, including long non-coding RNAs (lncRNAs) to enhance viral reactivation while minimizing toxicity. Future strategies will prioritize combinatorial approaches integrating epigenetic, immunologic, and transcriptional regulation to eliminate latent reservoirs. Elucidation of NF-κB sub-pathways and regulatory networks will be critical for developing safe and effective HIV cure strategies.