SLFN12 Expression is Found in Cells Positive for HIV Transcripts But Negative for HIV Protein


A barrier in effectively treating HIV has been the latency of infected CD4+ T cells, which are often treatment-resistant and contribute to the persistence nature of the virus.

SLFN12 expression is potent in cells that are infected and positive for HIV transcripts, but negative in HIV proteins. Investigators found that codon-usage dependent translation inhibition of HIV proteins can contribute to the latency of the virus, restricting the amount of HIV that is released after latency reversal, according to the results of a study published in Community Biology.

Image Credit: Adobe Stock - tashatuvango

Image Credit: Adobe Stock - tashatuvango

A barrier of treatment for HIV has been the latency of infected CD4+ T cells, which are often treatment-resistant and contribute to the persistent nature of the virus despite combination antiretroviral therapy and antiviral immune responses. The mechanisms of the latency have been previously unknown.

Study investigators analyzed different genes that were expressed in the primary CD4+ T cells, either cultured by homeostatic proliferation or after T cell receptor stimulation in order to decipher the mechanisms that contributed to the refractory state of HIV.

The naïve CD4+ T cells were purified from peripheral blood mononuclear cells, which were acquired from 3 HIV uninfected blood doners and cultured in 4 different ways.

The 4 ways included homeostatic proliferation and T cell receptor stimulations; not stimulated with T cell; 2 T cell receptor stimulations; 1 T cell receptor stimulation.

RNA was collected by the investigators form the cultured cells. To confirm the results, investigators gathered samples from 5 additional blood doners who were healthy and cultured the samples under the same conditions.

Investigators found that the expression pattern was consistent with the RNA-sequence analysis, and they found it differed from other SLFN family mRNAs. The other SLFNs did not show a trend toward a decrease from homeostatic proliferation and T cell receptor stimulations to T cell receptor stimulations culture conditions.

Investigators also found that the mechanism actions of SLFN1 2 were similar to those for SLFN11, even with the limited sequence homology between them, according to the results of the study. Even with the differences in transcription patterns, investigators believe that the antiviral function redundancy could help provide a way to control the virus within different cell growth conditions.

Given that, investigators also believe that SLFN12 is an important part of the post-transcriptional block, enabling HIV-infected cells to become undetectable to adaptive immune responses and antiviral therapies. Investigators also said that blocking SLFN11 and SLFN12 functions could increase the viral protein production, which could ultimately bring more HIV-infected cells to the forefront, making the cells more susceptible to the immune system as well as antiviral drugs.

Furthermore, the results of the study show that the mechanisms that allow SLFN12 to inhibit HIV can restrict latency reversal in a codon usage-dependent manner. Investigators said that both SLFN11 and SLFN12 were comparable anti-HIV properties, allowing it to evade active site mutations in the proteins’ RNase domains.

There was also a correlation between SLFN12 expression and HIV viral load, which indicates a possible link with the 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,” the study authors concluded. “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.”


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

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