A Yale research team announced on Mar. 13 that they have discovered a circular RNA produced by human immunodeficiency virus (HIV) which helps the virus activate its genes and replicate more efficiently. The study, led by immunologist Grace Chen, was published in Nature Microbiology.
The discovery of this circular RNA, named "circHIV," could provide a new target for future HIV therapies. Circular RNAs differ from typical linear RNAs because they lack distinct ends and are more stable, making them harder to degrade.
Chen began the project in 2019 with graduate student Prisca Obi and postdoctoral researcher Lichong Yan. After sequencing RNA from HIV-infected cells, the team found that HIV encodes several circRNAs, including the abundantly expressed circHIV. They detected these structures not only in infected human cells but also in blood plasma from people living with HIV.
Further experiments showed that reducing levels of circHIV lowered HIV gene activity, while increasing it had the opposite effect. Protein-binding studies revealed that circHIV binds to the Tat protein of HIV, which helps explain how it boosts viral transcription so effectively.
The research faced delays due to the COVID-19 pandemic, but Chen said her team remained committed during lockdowns: "We had four to six months of just brainstorming ideas when we were working from home. We couldn't wait to get back in the lab and test them out." When control samples were needed after returning to work, Chen said, "The team was so committed that every one of us gave our own plasma to be negative controls, and a doctor down the hall from my lab drew our blood."
Chen credits her background in chemical biology and molecular biology for inspiring her interest in unusual RNAs produced by viruses. She emphasized the multidisciplinary nature of the project: "This is a truly multidisciplinary group, both within my own lab and with our collaborators, and it really represents the spirit of this work," adding gratitude for "the generosity of this community."
Reflecting on her field's progress since landmark papers identified abundant circRNAs in eukaryotes over a decade ago, Chen said: "I was enthralled by the idea that we'd been looking at RNA for so long and we'd missed an entire category... We've been trying to understand the biology of HIV for decades. And now we've discovered something new about it. I never bet against RNA. It has a way of doing things that surprise you."
