Inhibition of salt inducible kinases reduces rhythmic HIV-1 replication and reactivation from latency

Human immunodeficiency virus type 1 (HIV- 1) causes a major burden on global health, and eradication of latent virus infection is one of the biggest challenges in the field. The circadian clock is an endogenous timing system that oscillates with a similar to 24 h period regulating multiple physiological processes and cellular functions, and we recently reported that the cell intrinsic clock regulates rhythmic HIV- 1 replication. Salt inducible kinases (SIK) contribute to circadian regulatory networks, however, there is limited evidence for SIKs regulating HIV- 1 infection. Here, we show that pharmacological inhibition of SIKs perturbed the cellular clock and reduced rhythmic HIV- 1 replication in circadian synchronised cells. Further, SIK inhibitors or genetic silencing of Sik expression inhibited viral replication in primary cells and in a latency model, respectively. Overall, this study demonstrates a role for salt inducible kinases in regulating HIV- 1 replication and latency reactivation, which can provide innovative routes to better understand and target latent HIV- 1 infection.

Automated summary

Human immunodeficiency virus type 1 (HIV-1) poses a significant global health burden, and eradicating latent virus infection is a major challenge. The circadian clock, an internal timing system, regulates HIV-1 replication. Salt inducible kinases (SIK) contribute to this regulation, and inhibiting SIKs disrupts the cellular clock and reduces rhythmic HIV-1 replication. This study demonstrates the role of SIKs in regulating HIV-1 replication and latency reactivation, providing insights for understanding and targeting latent HIV-1 infection.