Epigenetic regulation of HIV-1 transcription: insights into latency mechanisms and therapeutic strategies.

HIV-1 is one of the most serious pathogens currently threatening human health worldwide. Although antiretroviral therapy (ART) effectively suppresses HIV-1 replication, it fails to eliminate the latent reservoir of transcriptionally silent proviruses that persist in long-lived cells, making HIV-1 latency the major obstacle to achieving a functional cure for AIDS. The establishment and reversal of HIV-1 latency are largely regulated by epigenetic regulatory mechanisms involving the viral long terminal repeat (LTR) promoter. Following proviral integration into the host genome, the viral DNA is rapidly assembled into chromatin, where nucleosome positioning and diverse epigenetic modifications regulate viral transcription activity. At the chromatin level, nucleosome positioning at the LTR contributes to constrained transcriptional accessibility. In addition, coordinated histone methylation and DNA methylation promote transcriptionally repressive states, whereas histone acetylation dynamics facilitate chromatin relaxation and transcriptional reactivation in response to cellular stimuli. Beyond these classical mechanisms, emerging studies highlight additional regulatory mechanisms, including histone crotonylation and non-coding RNA, which further regulate HIV-1 epigenetic control. These mechanisms constitute a multilayered regulatory network that enables both stability of latency and potential reactivation upon perturbation. These lines of evidence not only help elucidate the mechanisms underlying the establishment and maintenance of latency, but also support the development of effective strategies to target latent reservoirs. This review synthesizes current understanding of how chromatin organization and epigenetic regulation modulates the establishment, maintenance and reactivation of HIV-1 latency, and discusses prospective epigenetic-targeting strategies for latent reservoir elimination.