HIV-1's Hidden Strategy: Circular RNAs Enable Virus to Evade the Immune System

Researchers from Florida Atlantic University’s Charles E. Schmidt College of Medicine have uncovered a novel mechanism by which HIV-1, the virus responsible for AIDS, evades the body’s immune defenses and sustains its replication. This discovery centers around the production of circular RNAs (circRNAs), a unique form of RNA that forms a covalently closed loop, making it significantly more stable than linear RNAs. Unlike typical RNA molecules that have ends, circRNAs are shaped like circles, allowing them to act as molecular sponges by soaking up microRNAs (miRNAs) and preventing these miRNAs from regulating gene expression.

While circRNAs have been extensively studied in human and animal cells—especially in large DNA viruses such as herpesviruses—this is the first evidence demonstrating that an RNA virus like HIV-1 can generate these stable looped RNAs. The study, published in npj Viruses, shows that HIV-1 produces at least 15 distinct circRNAs from its integrated genome, confirmed through advanced sequencing and molecular techniques.

In the context of infection, immune cells called CD4+ T cells respond by increasing levels of specific microRNAs—namely miR-6727-3p and miR-4722-3p—that are believed to help fight the virus. However, HIV-1 counters this defense by producing circRNAs that trap these microRNAs, reducing their activity. This neutralization diminishes the immune response, allowing the virus to replicate more efficiently and potentially leading to longer survival within the host. Notably, one of the prominent circRNAs, named Circ23, incorporates sections of the viral genome previously not well understood, but now recognized as crucial for viral persistence.

Further analysis suggests that the production of these circRNAs may vary among individuals, influenced by how host cells process RNA and by the availability of RNA-binding proteins necessary for circRNA formation. Such variations could explain differences in viral latency and disease progression among patients. Since circRNAs are notably stable and specific, they hold promise as biomarkers for infection and targets for innovative therapies.

The research points toward new therapeutic avenues, including using antisense oligonucleotides (ASOs) to block HIV-1 circRNAs, thereby restoring immune function and preventing the virus from hiding. Understanding and disrupting this circRNA-mediated tactic could be a vital step in overcoming HIV's resilience and moving closer to a cure.

“This discovery reveals a sophisticated way HIV manipulates human cells,” said senior author Dr. Massimo Caputi. “Targeting these viral circRNAs may open new pathways for treatment, as they could serve both as markers and as novel drug targets.”

This groundbreaking finding enhances our understanding of HIV biology and underscores the importance of circRNAs in viral persistence, highlighting their potential role in future antiviral strategies.