SLFN12 identified as a novel HIV restriction factor, paving the way for improved therapeutic strategies

Researchers from the Infection Biology and Molecular Virology laboratories at MELIS-UPF have led an international study that has identified and characterized Schlafen 12 (SLFN 12) as a new HIV restriction factor. The research found that SLFN 12 inhibits viral protein production, allowing virus-infected cells to evade anti-HIV therapy and immune responses. This discovery provides new insights into the development of therapeutic strategies for the treatment and potential cure of HIV infections.

HIV infections lead to the gradual destruction of the immune system, resulting in AIDS if left untreated. Annually, 650,000 people die from AIDS worldwide, making it a significant threat to human health. Although appropriate antiretroviral therapy can enable people with HIV to live relatively healthy lives, the virus can return from a reservoir of latently infected cells if treatment is stopped.

Latency is a significant obstacle to eliminating the virus in HIV-infected individuals. To cure an existing infection, it is necessary to eliminate latently infected cells. This makes it critical to understand how latency works, according to Andreas Meyerhans, ICREA research professor at UPF, who coordinated the study alongside Juana Díez.

The study, published in Communications Biology, identified and characterized SLFN12, a protein that restricts viral protein production by cleaving specific cellular tRNAs, the building blocks for protein construction. As a result, HIV-infected CD4 T cells cannot complete the virus production process in the presence of active SLFN12. Instead, the cells keep the templates for HIV RNA in a latent state.

Mie Kobayashi-Ishihara, the manuscript’s first author, said, “SLFN12 impairs protein production, restricting the production of viral particles. Such cells are latently infected, invisible to the immune system and anti-HIV therapies.”

The study also demonstrated how SLFN12 can selectively inhibit HIV protein production without blocking cellular protein production. Juana Díez explained, “SLFN12 cleaves Leucine-UUA tRNA, a building block that is rarely used for cellular proteins but essential for HIV viral proteins.”

The discovery creates opportunities to design new therapeutic strategies against HIV. “Blocking SLFN12 antiviral functions should increase viral protein expression, and thus enable the host immune system and antiviral drugs to better eliminate viral reservoirs. Once you start producing the virus, it becomes visible again. You get your target back. So, you can attack it and hopefully eliminate the latently infected cells,” Meyerhans said.

The Schlafen family of proteins, involved in cancer, drug sensitivity, and antiviral functions, takes its name from the German word “schlafen,” meaning “sleeping.”

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