Indian scientists have identified a specific RNA that plays a vital role in HIV virus replication making the virus escape the immune barriers. The breakthrough research by scientists at Indian Institute of Science Education and Research (IISER), Bhopal reveals how by blocking a circular RNA (ribonucleic acid) molecule ‘ciTRAN’, HIV virus replication in humans can be inhibited.
The circular RNA ciTRAN influences the transcription process of HIV virus and thus helps the virus replication in the human body. The Bhopal researchers have discovered the mechanism through which HIV virus escapes the inhibition barrier and thus have paved a way for further research in controlling the HIV replication process.
According to the data with World Health Organization’s Global HIV Observatory, there are over 39 million persons living with HIV as of 2022. The AIDS-causing HIV infection has remained the world’s most significant public health challenge.
What is circular RNA ciTRAN?
The research by IISER scientists has shown that the HIV virus uses the circular RNA ciTRAN to overcome the transmission barriers, by regulating a protein in the human body called SRSF1, that inhibits HIV.
The five -year research, which began in 2018, has now been published in the recent edition of journal Science Advances. The study was conducted by IISER scientists Vipin Bhardwaj, Aman Singh, Aditi Choudhary, Rishikesh Dalavi, Lalchhanhima Ralte, Richard Chawngthu, Nachimuthu Senthilkumar, Nagarjun Vijay and Ajit Chande.
Speaking to Happiest Health, Ajit Chande, Assistant Professor, department of Biological Sciences explains that the protein SRSF1 is known to inhibit HIV, but so far, there was no molecular mechanism to explain how the HIV virus prevents the inhibition of SRSF1. If the virus is successfully replicating, it must have a mechanism to evade or antagonize the SRSF1 function.
“Now we know that the virus induces the circular RNA ciTRAN and makes more copies of it so as to keep the SRSF1 protein away from the HIV transcription machinery. Thus, viral transcription can continue, and virus can multiply efficiently. Virus essentially hijacks the circular RNA and uses it for its own purpose for efficient replication,” said Chande.
The researchers developed a novel approach called ‘circDR-Seq’, through which they depleted the pool of linear RNA and identified ciTRAN. “We noticed that suddenly the HIV -1 virus stopped replicating. With this, we have found out that in the absence of the ciTRAN, HIV can not replicate,” Chande explained.
While there are two HIV viruses known as HIV-1 and HIV-2, the researchers worked on HIV-1 virus, which has a higher pathogenicity compared to that of HIV-2. “We have very strong data on this HIV-1 virus specific adaptation. No experimentation has been done on HIV-2,” said Chande.
How ciTRAN research can help HIV patients?
The circular RNA ciTRAN is detected in those living with HIV. The research may lead to novel insights which may help in designing molecules for controlling virus replciation, the scientists said.
Prof Gobardhan Das, Director, IISER Bhopal, expressed his excitement over this pivotal discovery. “This work opens up new lines of investigations and may provide new leads for host-directed treatments,” Prof Das added.
The researchers have also developed inhibitors in the form of a molecule that blocks the circular RNA, which is one of the ways to silence the virus from replicating.
“Our inhibitor is occupying the binding site on the circular RNA. Thus, the SRSF1 is no longer binding and hence it is free to inhibit the virus and virus replication,” the researchers explained Happiest Health.
“We have proof of concept now. A small protein that we have engineered is capable of suppressing HIV replication. More work is needed for drug delivery,” said Chande.
When the research began in the year 2018, the researchers were curious to understand why the circular RNA exists. “There was not a single report about the circular RNA at that time in HIV field. We are lucky to report it for the first time pertaining to the function of a circular RNA in HIV. We started with very preliminary data that we had based on the characterization of few known circular RNA in the context of HIV replication,” said Chande.
The researchers received substantial funding from the DBT/Wellcome Trust India Alliance for their study.
In a breakthrough research, scientists from Indian Institute of Science Education and Research, Bhopal have discovered that the circular RNA, which has now been coined as ciTRAN, can modulate the virus replication. The new research has also given hopes for possible pharmaceutical research to inhibit HIV replication.