Long Noncoding RNA LINC02453 Inhibits HIV‐1 Replication by Binding With SEC13 to Regulate the Viral Productive Cycle

ABSTRACT Emerging evidence underscores the pivotal role of long noncoding RNAs (lncRNAs) as crucial regulators within the HIV life cycle. However, the precise functions and detailed mechanisms by which lncRNAs operate in HIV‐1 highly exposed but persistently seronegative (HESN) individuals remain currently unknown. Through RNA sequencing analysis of the HESN individual and the matched control, we identified potential lncRNAs. Then, we conducted validation experiments at the population level, while cellular models of HIV‐1 infection were constructed for functional experimental investigations in vitro. Subcellular localization of the identified lncRNA was determined, followed by an exploration of the specific regulatory mechanism underlying HIV resistance through some experiments, such as RNA pull‐down, western blot and Hirt assays. LncRNA LINC02453 is highly expressed in HESN. Moreover, LINC02453 is identified as a novel lncRNA associated with heightened resistance to HIV‐1. LINC02453 is predominantly localized in the nucleus and binds to SEC13, a component of the nuclear pore complex, leading to the inhibition of HIV‐1 replication by regulating key processes such as late reverse transcription, nuclear import, and DNA integration. Our findings suggest that LINC02453 may serve as a prospective target for the development of innovative anti‐HIV therapeutics.