Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells
Mie Kobayashi‐Ishihara, Katarína Frazão Smutná, Florencia E. Alonso, Jordi Argilaguet, Anna Esteve‐Codina, Kerstin Geiger, Meritxell Genescà, Judith Grau-Expósito, Clara Duran-Castells, Selina Rogenmoser, René Böttcher, Jennifer Jungfleisch, Baldomero Oliva, Javier P. Martínez, Manqing Li, Michael David, Makoto Yamagishi, Marta Ruiz‐Riol, Christian Brander, Yasuko Tsunetsugu‐Yokota, María J. Buzón, Juana Díez, Andreas Meyerhans
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.