The “loophole?” A biological process that involves circular RNAs (circRNAs), which form a “loop” or circle inside cells – unlike regular RNA molecules that are shaped like a straight line. This looped shape makes circRNAs much more stable and enables them to act like sponges – soaking up microRNAs (miRNAs) and preventing them from doing their usual jobs such as controlling which genes get turned on or off.
Although scientists have previously discovered thousands of circRNAs in human and animal cells, only a small number have been found in viruses – mainly in large DNA viruses like herpesviruses, including Herpes Simplex Virus and Epstein-Barr Virus. These viruses have big genomes and can stay hidden in the body for years before becoming active again.
Results of the study, published in the journal npj Viruses, marks the first experimental evidence of HIV-1 generating circRNAs produced from an integrated retroviral genome, offering a new perspective on HIV biology. These findings reveal a previously hidden layer of HIV-1’s life cycle, shedding light on how the virus enhances its persistence, replication and ability to evade the immune system. They also point to a novel strategy the virus uses to survive, offering researchers a new target in the fight against one of the world’s most resilient pathogens.
“We’ve known that circular RNAs show up in DNA viruses like Epstein-Barr and the human papillomavirus, but seeing that they are generated by an RNA virus like HIV-1 is incredibly exciting,” said Massimo Caputi, Ph.D., senior author and a professor in the Department of Biomedical Science, Schmidt College of Medicine. “HIV-1 is unique – it integrates into the host genome and hijacks the cell’s RNA-processing machinery, giving it a rare ability among RNA viruses to generate these stable circular RNAs.”
The team identified at least 15 distinct 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 respond by increasing levels of two microRNAs – miR-6727-3p and miR-4722-3p – that likely help fight the virus,” said Caputi. “But HIV seems to fight back by producing circRNAs that trap these microRNAs. This weakens the immune response and helps the virus make more copies of itself. This suggests that HIV’s circular RNAs might help keep infected cells alive and allow the virus to stay hidden in the body for a long time – one of the main reasons why HIV is so hard to cure.”
Normally, certain miRNAs are present at low levels, but they increase when a person is infected with HIV. To fight back, HIV makes circRNAs that soak up these miRNAs and weaken the body’s defense. This allows the virus to keep multiplying.
“One of the most common circRNAs made by HIV, called Circ23, includes parts of the virus’ genetic code that scientists didn’t fully understand before,” said Caputi. “But now, they seem important for helping the virus survive and replicate.”
The findings also suggest that circRNA production may vary between individuals, potentially influencing differences in viral persistence and spread. This variation could stem from how host cells process RNA and from the availability of RNA-binding proteins needed to form circRNAs.
“These differences may help explain why patient responses vary, especially in cases of viral latency – a state where the virus lies dormant and resists both immune attack and antiretroviral therapy,” said Caputi.
Although current techniques make it difficult to measure circRNAs accurately, the researchers note that the use of droplet digital PCR may soon allow precise quantification of these molecules in patient samples.
“This is just the beginning,” said Caputi. “We’re now working to map out how these viral circular RNAs interact with human cells. If we can figure out how to block them, we might be able to stop the virus from hiding and help move closer to a cure.”
The research team also plans to explore new treatments that use special molecules called antisense oligonucleotides (ASOs) to block HIV’s circRNAs. They’ll test this approach in models of long-term infection and in cells from people living with HIV to better understand how these circRNAs help the virus survive in the body.
“Our findings reveal how HIV takes control of human cells at a very detailed level and point to new possibilities for treatment,” said Caputi. “Because circular RNAs are stable and specific, they could also be used as markers of infection or as new targets for drugs.”
Study co-authors are Christopher Mauer and Sean Paz, graduate students in the FAU Department of Biomedical Science.
- FAU -
About the Charles E. Schmidt College of Medicine:
Florida Atlantic University’s Charles E. Schmidt College of Medicine is one of approximately 159 accredited medical schools in the U.S. The college was launched in 2010, when the Florida Board of Governors made a landmark decision authorizing FAU to award the M.D. degree. After receiving approval from the Florida legislature and the governor, it became the 134th allopathic medical school in North America. With more than 170 full and part-time faculty and more than 1,300 affiliate faculty, the college matriculates 80 medical students each year and has been nationally recognized for its innovative curriculum. The college offers M.S. (thesis and non-thesis) and Ph.D. programs in biomedical science, along with a certificate in genomics and precision medicine. Taught by top researchers, the curriculum combines cutting-edge coursework with hands-on learning, preparing graduates for careers in medicine, research, industry, and academia. To further Florida Atlantic’s commitment to increase much needed medical residency positions in Palm Beach County and to ensure that the region will continue to have an adequate and well-trained physician workforce, the FAU Charles E. Schmidt College of Medicine Consortium for Graduate Medical Education (GME) was formed in fall 2011 with five leading hospitals in Palm Beach County. The consortium currently has five Accreditation Council for Graduate Medical Education (ACGME) accredited residencies including internal medicine, surgery, emergency medicine, psychiatry, and neurology, and five fellowships in cardiology, hospice and palliative care, geriatrics, vascular surgery, and pulmonary disease and critical care medicine. The college also manages the Florida Atlantic University Medical Group, offering comprehensive primary care, and the Marcus Institute of Integrative Health specializes in integrative pain management, precision therapies, and mental health. A 2023 partnership with Broward Health expands academic medicine, clinical training, and research opportunities.
About Florida Atlantic University:
Florida Atlantic University, established in 1961, officially opened its doors in 1964 as the fifth public university in Florida. Today, Florida Atlantic serves more than 30,000 undergraduate and graduate students across six campuses located along the Southeast Florida coast. In recent years, the University has doubled its research expenditures and outpaced its peers in student achievement rates. Through the coexistence of access and excellence, Florida Atlantic embodies an innovative model where traditional achievement gaps vanish. Florida Atlantic is designated as a Hispanic-serving institution, ranked as a top public university by U.S. News & World Report, and holds the designation of “R1: Very High Research Spending and Doctorate Production” by the Carnegie Classification of Institutions of Higher Education. Florida Atlantic shares this status with less than 5% of the nearly 4,000 universities in the United States. For more information, visit www.fau.edu.
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