HIV uses circular RNA to avoid immunity and promote replication

In a groundbreaking discovery, researchers at the Charles E. Schmidt College of Medicine at Florida Atlantic University have identified an unprecedented mechanism that allows human immunodeficiency virus (HIV-1) to avoid the body's natural defenses and use it to support survival and replication.

“Loop hole?” Unlike regular RNA molecules shaped like a straight line, a biological process involving circular RNA (CIRCRNA) that forms a circle of “loops” or circles within a cell. This looped shape makes the Silna much more stable and can act like a sponge. It soaks microRNAs (miRNAs) to prevent them from doing normal tasks such as which genes are turned on or off.

Scientists have previously discovered thousands of Silkana in human and animal cells, but only a small number of viruses have been discovered in large DNA viruses, mainly herpes simplex and herpes viruses, including Epstein Barr viruses. These viruses have large genomes that can be left hidden in the body for years before they can re-activate.

The results of the study published in the journal NPJ Virus present the first evidence of HIV-1, which generates CircrNA generated from the integrated retroviral genome, providing a new perspective on HIV biology. These findings reveal previously hidden layers of the HIV-1 lifecycle and shed light on how the virus enhances its persistence, replication and ability to avoid the immune system. They also point out new strategies the virus uses to survive, providing researchers with new targets in the fight against one of the world's most resilient pathogens.

We know that circulating RNAs appear in DNA viruses such as Epstein Barr and human papillomaviruses, but it is very exciting to be produced by RNA viruses like HIV-1. HIV-1 is unique – it consolidates into the host genome, hijacks cellular RNA processing machines, and gives it the unusual ability to generate these stable circular RNAs among RNA viruses. ”

Massimo Caputi, Ph.D. , Senior Author and Professor, Department of Biomedical Science, Schmidt School of Medicine

The team identified at least 15 different HIV-1 CircrNAs and confirmed their presence using advanced molecular techniques and sequencing tools.

“When HIV infects the body, certain immune cells called CD4+ T cells Caputi said: However, HIV appears to be fighting back by generating Silkna that captures these microRANAs. This weakens the immune response and helps the virus increase its own copy. This suggests that HIV's circular RNAs can help keep infected cells alive and ensure that the virus remains hidden in the body for a long time. This is one of the main reasons why HIV is difficult to cure. ”

Typically, certain miRNAs are present at low levels, but increase when a person infected with HIV. To fight back, HIV absorbs these miRNAs and creates Silkna that weakens the body's defenses. This will allow the virus to continue to multiply.

“One of the most common silkna produced by HIV, called circ23, contains some of the genetic codes of viruses that scientists previously had not fully understood,” Caputi said. “But now they seem important to help the virus survive and replicate.”

The findings also suggest that silkuna production may differ from person to person, potentially affecting differences in viral persistence and spread. This variation can be attributed to the way host cells process RNA and the availability of RNA-binding proteins required to form circrNA.

“These differences may help explain why patients respond differently, especially when they are at viral latency: the virus becomes dormant and resists both immune attack and antiretroviral therapy,” Caputi said.

Although current methods make accurate measurements of silna, researchers note that the use of droplet digital PCR may soon allow for accurate quantification of these molecules in patient samples.

“This is just the beginning,” Caputi said. “We are currently working to map how the circular RNAs of these viruses interact with human cells. If we can find ways to block them, we may be able to keep the viruses from covering and help them get closer to treatment.”

The researchers will also explore new treatments that use a special molecule called antisense oligonucleotides (ASOS) to block HIV silna. They test this approach in models of long-term infection and cells of people living with HIV, and will better understand how these silknae help the virus survive in the body.

“Our findings reveal how HIV regulates human cells at a very detailed level and points to new possibilities for treatment,” Caputi said. “Round RNAs are stable and specific, so they can be used as markers of infection or as new targets for drugs.”

The study co-authors are Christopher Mauer and Shawn Pass, graduate students of the FAU Faculty of Biomedical Sciences.