Yale researchers identify circular RNA that boosts HIV replication
Scientists at Yale University have discovered that HIV produces a circular RNA molecule that helps the virus activate its genes and replicate more efficiently. The finding reveals a previously unknown layer of HIV biology and could open new avenues for antiviral therapies.
The study, published on March 12 in Nature Microbiology, identified a loop-shaped RNA molecule named circHIV. Researchers detected the molecule in the plasma of 18 people living with HIV as well as in infected primary cells and T-cell lines. Experiments showed that circHIV binds to the HIV-1 Tat protein and enhances transcription from the viral promoter, enabling the virus to increase its own gene expression.
The research was led by immunologist Grace Chen, an assistant professor of immunobiology and genetics at Yale School of Medicine. Chen’s laboratory focuses on circular RNAs, a class of RNA molecules that form closed loops rather than the linear strands commonly produced during gene expression.
Chen began the project in 2019 with graduate student Prisca Obi and associate research scientist Lichong Yan, who served as co first authors of the study. The team suspected HIV-1 could generate circular RNA because, unlike most RNA viruses, it integrates into the host genome and uses the host cell’s transcription and splicing machinery.
Using RNA sequencing in cell lines containing integrated HIV-1 genomes, the researchers identified nine viral circular RNAs distributed across the HIV genome. They selected the most abundant molecule for detailed analysis and named it circHIV.
Functional experiments demonstrated that reducing circHIV levels lowered viral infection rates. In contrast, introducing a synthetic version of the circular RNA increased viral replication. Further analysis revealed that circHIV and another RNA element known as TAR both bind to the Tat protein independently rather than competing for the same binding site. This observation suggests Tat may contain a previously unidentified domain capable of interacting with circular RNA.
The findings challenge a long standing assumption that retroviruses generate only linear RNA transcripts. Circular RNAs have previously been identified in large DNA viruses such as herpesviruses and Epstein-Barr virus, but evidence for similar molecules in RNA viruses has been limited.
A separate 2025 study by researchers at Florida Atlantic University reported circular RNAs produced by HIV-1 that act as molecular “sponges” for host microRNAs. The Yale research is the first to demonstrate that a viral circular RNA directly promotes HIV transcription by interacting with the Tat protein.
Circular RNAs are structurally stable because they lack the free ends that make linear RNA vulnerable to degradation. This stability allows them to persist longer in cells, a property that could make them useful as diagnostic biomarkers or therapeutic targets.
The Yale team also observed that circHIV becomes packaged into HIV-1 virions and is present both in the nucleus and the cytoplasm of infected cells. These characteristics suggest the molecule may play multiple roles in the viral life cycle.
Progress on the project slowed during the COVID-19 pandemic, which interrupted laboratory work shortly after the researchers confirmed the circular RNA back-splicing junction in February 2020. According to the team, members of the laboratory volunteered their own blood samples as negative controls to help complete the experiments.
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