Breakthrough Discovery: Circular RNA's Role in HIV Replication Unveiled by IISER Bhopal Scientists

Scientists from the Indian Institute of Science and Research (IISER) in Bhopal have unveiled a groundbreaking discovery that may revolutionize AIDS treatment. Their research sheds light on a circular ribonucleic acid (RNA) molecule called ciTRAN, which aids the multiplication of the HIV-1 virus, the predominant strain of human immunodeficiency virus (HIV) responsible for AIDS.

HIV-1 is notorious for attacking the body's immune system, eventually leading to AIDS, a life-threatening condition. However, the recent findings by IISER scientists offer new hope in the battle against this deadly disease.

In a study published in the prestigious Science Advances journal on September 6, the researchers revealed the pivotal role played by ciTRAN in facilitating HIV replication. RNA, a vital genetic material akin to DNA, performs various functions, including genetic information transportation and protein production. There are two primary RNA categories: linear and circular. Circular RNAs, like ciTRAN, exhibit altered behavior when the body's immune system responds to infection or inflammation.

While circular RNAs are known indicators of viral transmission systems, their exact involvement in HIV infection remained a mystery until this study. The IISER scientists' groundbreaking research has connected circular RNAs to HIV replication, uncovering a critical link in the virus's spread throughout the body. Furthermore, the study pinpointed a specific circRNA subtype that contributes to this process.

Remarkably, the researchers also identified how HIV exploits ciTRAN's RNA code, deactivating a crucial protein within the RNA molecule designed to inhibit HIV replication. Intriguingly, only HIV molecules accompanied by the accessory protein Vpr possess the capability to infiltrate ciTRAN RNA molecules.

Lead researcher Ajit Chande emphasized the novelty of their work, stating, "There have been several studies on cancer and circular RNAs, but none on HIV replication. Ours is the first."

The discovery holds immense promise for advancing host-directed treatments. IISER Director Gobardhan Das noted in a press release that this breakthrough "opens up new lines of investigations and may provide new leads for host-directed treatments."

Key Findings:

Chande's team employed nanopore direct RNA sequencing, known as circDR-Seq, to isolate and study circular RNA molecules infected with HIV-1. Given that linear RNAs are vastly more common than circular RNAs in specialized immune system cells called T-cells, the researchers meticulously removed various linear RNA types from T-cells, leaving behind the circular RNAs for analysis.

Further refining the RNA mix, they increased the concentration of circular RNAs to pinpoint those involved in HIV viral replication. Utilizing CRISPR-Cas9 technology, they confirmed that ciTRAN RNA molecules indeed facilitated HIV multiplication. HIV manipulates ciTRAN RNA to disable the "stop switch" for HIV replication, represented by a protein called SRSF1.

Essentially, ciTRAN assists the HIV virus in propagating its genetic information and synthesizing viral proteins. Notably, ciTRAN neutralizes the inhibitory protein SRSF1, which usually curbs HIV replication. The study also identified an accessory protein, Vpr, found within HIV cells, which is essential for the virus to hijack ciTRAN.

This research is a significant step forward in developing treatments for HIV. It demonstrates that while HIV can thwart SRSF1, synthetic molecules mimicking the SRSF1 structure can be employed to fulfill its role of suppressing HIV replication.

In conclusion, the IISER scientists' groundbreaking discovery of the role of ciTRAN in HIV replication presents a promising avenue for future research and potential breakthroughs in HIV treatment. This vital advancement may pave the way for innovative therapies and, ultimately, a more effective approach to combating AIDS.