NF-ĸB-Interacting Long Noncoding RNA Regulates HIV-1 Replication and Latency by Repressing NF-ĸB Signaling.

NF-ĸB-interacting long noncoding RNA (NKILA) was recently identified as a negative regulator of NF-ĸB signaling and plays an important role in the development of various cancers. It is well known that NF-ĸB-mediated activation of human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-driven gene expression is required for HIV-1 transcription and reactivation of latency. However, whether NKILA plays essential roles in HIV-1 replication and latency is unclear. Here, by ectopic expression and silencing experiments, we demonstrate that NKILA potently inhibits HIV-1 replication in an NF-ĸB-dependent manner by suppressing HIV-1 LTR promoter activity. Moreover, NKILA showed broad-spectrum inhibition on the replication of HIV-1 clones with different coreceptor tropisms as well as on LTR activity of various HIV-1 clinical subtypes. Chromatin immunoprecipitation (ChIP) assays revealed that NKILA expression abolishes the recruitment of p65 to the duplicated ĸB binding sites in the HIV-1 LTR. NKILA mutants disrupting NF-ĸB inhibition also lost the ability to inhibit HIV-1 replication. Notably, HIV-1 infection or reactivation significantly downregulated NKILA expression in T cells in order to facilitate viral replication. Downregulated NKILA was mainly due to reduced acetylation of histone K27 on the promoter of NKILA by HIV-1 infection, which blocks NKILA expression. Knockdown of NKILA promoted the reactivation of latent HIV-1 upon phorbol myristate acetate (PMA) stimulation, while ectopic NKILA suppressed the reactivation in a wellestablished clinical model of withdrawal of azidothymidine (AZT) in vitro. These findings improve our understanding of the functional suppression of HIV-1 replication and latency by NKILA through NF-ĸB signaling. [ABSTRACT FROM AUTHOR]