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

Kobayashi-Ishihara, Mie; Smutná, Katarína, 1991-; Alonso, Florencia E.; Argilaguet Marqués, Jordi, 1977-; Esteve-Codina, Anna; Geiger, Kerstin; Rogenmoser, Selina; Oliva Miguel, Baldomero; Martinez, Javier P.; Díez Antón, Juana, 1962-; Meyerhans, Andreas

doi:http://dx.doi.org/10.1038/s42003-023-04841-y

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

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Kobayashi-Ishihara M, Frazão Smutná K, Alonso FE, Argilaguet J, Esteve-Codina A, Geiger K, et al. Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells. Commun Biol. 2023 May 10;6(1):487. DOI: 10.1038/s42003-023-04841-y

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.