Despite antiretroviral therapies, HIV-1 persists in latent reservoirs: cells where the integrated viral genome (provirus) remains silent but potentially reactivatable. This latency prevents virus eradication. Understanding how proviral transcription is maintained in a dormant state is therefore a major challenge.
Argonaute proteins (Ago), numbering four in humans, are mainly known for their role in RNA interference via microRNAs, which regulate gene expression post-transcriptionally. Their involvement at the transcriptional level is much less documented, particularly for HIV-1.
Here, the authors show that Ago1 repression (knock-down) leads to reactivation of viral expression in different latency models. This reactivation correlates with an increase in nascent viral transcripts and a decrease in the repressive epigenetic mark H3K9me3 at the HIV-1 LTR promoter, indicating that Ago1 is associated with a silent chromatin state. Using imaging combining FISH and immunofluorescence, Ago1 was visualized accumulating at HIV-1 transcription sites, strengthening its role in controlling the viral promoter.
Biochemical analyses further demonstrate that Ago1 associates with chromatin via an RNA intermediary and interacts with RNA polymerase II (both initiating and elongating forms). However, Ago1’s effect is independent of microRNAs, and viral promoter elements (TAR, splice donor site SD1, polyadenylation signal) are not involved in this Ago1 function.
Together, these data reveal a non-canonical role of Ago1: beyond post-transcriptional RNA interference, Ago1 contributes to the transcriptional repression of latent HIV-1.
Reference
Goudey S, Said MA, Desforges J, Marie S, Morel M, Berlioz-Torrent C, Margottin-Goguet F, Emiliani S, Matkovic R, Gallois-Montbrun S. Argonaute 1 contributes to the transcriptional silencing of HIV-1. J Biol Chem. 2025 Aug 19:110612. doi: 10.1016/j.jbc.2025.110612. Epub ahead of print. PMID: 40840622.
