Invisible Threads: The Role of Circular RNAs in HIV Persistence

 

HIV-1 is still one of the most mysterious and persistent viruses, even after decades of research and antiretroviral treatments. The virus's capacity for effective replication, immune system evasion, and internal hiding is a key factor in its longevity. The ability of the virus to integrate into host DNA and create latent infections is well understood, but scientists have long speculated that it also uses other, secret biochemical mechanisms to help it live and grow. The mechanism by which HIV can impair the host's defenses at the RNA level, a layer of regulation that governs which genes are activated or deactivated during infection, has remained an open subject.

In an unexpected development, scientists have discovered a new method by which HIV-1 evades the immune system: it produces circular RNAs (circRNAs) from its own viral DNA. Non-linear RNA molecules known as circular RNAs are extremely robust and resistant to destruction because they form closed loops. Instead of acting as messengers for protein synthesis, circRNAs act as molecular sponges, absorbing tiny regulatory molecules known as microRNAs (miRNAs). CircRNAs were believed to be mostly found in cells and a few number of big DNA viruses until recently. HIV-1, an RNA virus, has a new and unidentified biological dimension thanks to the discovery that it can also produce circRNAs.

Normally, the body reacts to HIV infection of immune cells by raising the amounts of particular microRNAs that have protective functions. It is thought that two of these miRNAs, miR-6727-3p and miR-4722-3p, inhibit viral replication or improve immune response. These miRNAs, however, seem to be specially bound and trapped by the recently identified circRNAs generated by HIV. The circRNAs absorb the miRNAs and stop them from doing their antiviral work. In essence, this gives the virus the upper hand by neutralizing a part of the host's immune system. In addition to promoting viral replication, this process prolongs the life of infected cells, sustaining viral reservoirs that make total HIV eradication exceedingly challenging.

HIV-1 differs from other RNA viruses in that it incorporates its genome into the DNA of the host, giving it the ability to control the RNA-processing apparatus of the host cell. CircRNAs are created by looping sections of viral RNA through a process known as "backsplicing." At least 15 unique circular RNA molecules derived from the HIV genome have been discovered by researchers; one of these, called Circ23, may be crucial for immune evasion and viral persistence. Based on the way that each person's cells digest RNA and the presence of particular proteins that promote circularization, it is believed that different people produce different amounts of these circRNAs. This may contribute to the explanation of why some patients react differently to treatment or retain dormant viruses for longer than others.

Viral circRNAs are desirable targets for upcoming therapies due to their stability and specificity. In order to inhibit these circRNAs, researchers are investigating the use of antisense oligonucleotides, which are artificial compounds made to block RNA sequences. By preventing them from forming or functioning, the virus may be revealed, allowing the immune system and antiviral medications to more efficiently eradicate contaminated cells. Understanding this covert layer of RNA-based manipulation offers a viable avenue for better diagnosis, treatment, and eventually a cure in the fight against HIV.

REFERENCES

Mauer, C., Paz, S. & Caputi, M. Backsplicing of the HIV-1 transcript generates multiple circRNAs to promote viral replication. npj Viruses 3, 21 (2025). https://doi.org/10.1038/s44298-025-00105-0

IMAGE SOURCES

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