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

• Published in: Communications biology 2023-05, Vol.6 (1), p.487-487, Article 487
• Main Authors: Kobayashi-Ishihara, Mie, Frazão Smutná, Katarína, Alonso, Florencia E., Argilaguet, Jordi, Esteve-Codina, Anna, Geiger, Kerstin, Genescà, Meritxell, Grau-Expósito, Judith, Duran-Castells, Clara, Rogenmoser, Selina, Böttcher, René, Jungfleisch, Jennifer, Oliva, Baldomero, Martinez, Javier P., Li, Manqing, David, Michael, Yamagishi, Makoto, Ruiz-Riol, Marta, Brander, Christian, Tsunetsugu-Yokota, Yasuko, Buzon, Maria J., Díez, Juana, Meyerhans, Andreas
• Format: Article
• Language: English
• Subjects: 13/31; 38/109; 38/32; 38/39; 38/89; 631/250/255/1901; 631/326/596/2556; Acquired immune deficiency syndrome; AIDS; Antigens; Biology; Biomedical and Life Sciences; Cancer; CD4 antigen; CD4-Positive T-Lymphocytes; Cell lines; Codon Usage; Genes; HIV; HIV-1 - physiology; Human immunodeficiency virus; Immune system; Kinases; Latency; Latent infection; Life Sciences; Lymphocytes; Lymphocytes T; Medicine; Molecular biology; Phosphatase; Post-transcription; Proteins; Replication; Ribonuclease; RNA, Viral - genetics; T cell receptors; Virus Latency - genetics; Viruses
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-04841-y

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. In cell lines and HIV-1 patient PBMCs, the Schlafen 12 protein (SLFN12) is shown to be an HIV-1 restriction factor that inhibits HIV-1 replication and virus reactivation