Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells

Abstract

Latency is a major barrier towards virus elimination in HIV-1-infected individuals. Yet, the mechanisms that contribute to the maintenance of HIV-1 latency are incompletely understood. Here we describe the Schlafen 12 protein (SLFN12) as an HIV-1 restriction factor that establishes a post-transcriptional block in HIV-1-infected cells and thereby inhibits HIV-1 replication and virus reactivation from latently infected cells. The inhibitory activity is dependent on the HIV-1 codon usage and on the SLFN12 RNase active sites. Within HIV-1-infected individuals, SLFN12 expression in PBMCs correlated with HIV-1 plasma viral loads and proviral loads suggesting a link with the general activation of the immune system. Using an RNA FISH-Flow HIV-1 reactivation assay, we demonstrate that SLFN12 expression is enriched in infected cells positive for HIV-1 transcripts but negative for HIV-1 proteins. Thus, codon-usage dependent translation inhibition of HIV-1 proteins participates in HIV-1 latency and can restrict the amount of virus release after latency reversal.

Transfer RNA acetylation regulates in vivo mammalian stress signaling

“…While the rapid decay of hypomodified tRNAs is well-known in yeast, 9,67 in mammals these pathways are less extensively characterized. SLFN11 and SLFN12 are the most well-known regulators of type II tRNAs in mammals 68,69 but are not present in HEK-293T cells 70,71 raising the possibility of novel degradation mechanisms. Furthermore, we did not determine the precise cause of ribosome stalling in the absence of tRNA acetylation.…”

Overview of Structural and Functional Insights of SLFN12 Associated With Different Diseases

“…The researchers employ an RNA FISH-flow experiment to establish that the upregulation of SLFN12 is observed in HIV-1-infected cells that exhibit the presence of HIV-1 transcripts but lack the production of HIV-1 proteins. Therefore, the suppression of HIV-1 protein translation resulting from codon use plays a role in latency and can impede viral release following the reactivation of latent infection [23].…”