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

Kobayashi-Ishihara, M.; Smutna, K. F.; Alonso, F. E.; Argilaguet, J.; Esteve-Codina, A.; Geiger, K.; Genesca, M.; Grau-Exposito, J.; Duran-Castells, C.; Rogenmoser, S.; Böttcher, R.; Jungfleisch, J.; Oliva, B.; Martinez, J. P.; Li, M.; David, M.; Yamagishi, M.; Ruiz-Riol, M.; Brander, C.; Tsunetsugu-Yokota, Y.; Buzon, M. J.; Diez, J.; Meyerhans, A.

doi:10.1101/2022.11.09.512793

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bioRxiv · 10.1101/2022.11.09.512793

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

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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.

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Kobayashi-Ishihara, M., Smutna, K. F., Alonso, F. E., Argilaguet, J., Esteve-Codina, A., Geiger, K., Genesca, M., Grau-Exposito, J., Duran-Castells, C., Rogenmoser, S., Böttcher, R., Jungfleisch, J., Oliva, B., Martinez, J. P., Li, M., David, M., Yamagishi, M., Ruiz-Riol, M., Brander, C., Tsunetsugu-Yokota, Y., Buzon, M. J., Diez, J., Meyerhans, A.. 2022-11-09. Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells. https://doi.org/10.1101/2022.11.09.512793

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