Nikhil Prasad Fact checked by:Thailand Medical News Team Jun 10, 2024 1 month, 2 weeks, 3 days, 1 hour, 14 minutes ago
Medical News: In recent groundbreaking research, scientists have unveiled how our bodies' innate immune system, especially through the action of interferon-stimulated genes (ISGs), tackles dangerous retroviruses like HIV and HTLV-1. This study, conducted by a team of researchers from the German Primate Center and the Max Planck Institute and covered in this
Medical News report, highlights the vital role of ISGs in inhibiting viral translation, providing new hope for developing therapeutic approaches.
How Our Bodies Fight Retroviruses
Interferon-stimulated genes (ISGs) that inhibit viral translation. (1) Schlafen (SLFN) proteins degrade certain cellular tRNAs and rRNAs, which, in turn, inhibit viral translation. (2) Zinc finger antiviral protein (ZAP) binds eIF4A and prevents eIF4G binding, which is required for the formation of the eIF4G complex and translation initiation. The RNA-activated protein kinase (PKR) phosphorylates eIF2α and inhibits translation initiation by preventing eIF2B from generating functional eIF2–GTP from eIF2–GDP. (3) Shiftless (SFL) inhibits the −1PRF required for HIV-1 translation, potentially by recruiting eRF3-eRF1 to the ribosome at the slippery site and causing premature translation termination. (4) SFL inhibits the stop codon readthrough required for MLV translation by an unknown mechanism.
What Are Retroviruses?
Retroviruses, such as the human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV-1), are notorious for causing severe diseases in humans. These viruses integrate into our DNA and use our cellular machinery to replicate. However, our bodies have evolved sophisticated defense mechanisms, including the production of interferons (IFNs), which are proteins that help regulate the immune response and activate various ISGs to combat these viral invaders.
The Power of Interferons
Interferons play a crucial role in our first line of defense against viral infections. When a virus infects a cell, it triggers the production of interferons, which then activate ISGs. These ISGs encode proteins that can block different stages of the viral life cycle. There are three main types of interferons in humans: Type I (including IFN-α and IFN-β), Type II (IFN-γ), and Type III (IFN-λ). Each type interacts with specific receptors on the cell surface to initiate a signaling cascade that enhances the antiviral state of the cell.
Key Players: Schlafen, ZAP, PKR, and Shiftless
The study focuses on several ISGs that play significant roles in inhibiting the translation of retroviral mRNAs. These include Schlafen (SLFN) proteins, Zinc Finger Antiviral Protein (ZAP), RNA-activated protein kinase (PKR), and Shiftless (SFL).
-Schlafen Proteins: Schlafen proteins, particularly SLFN11, SLFN12, and SLFN13, inhibit viral protein synthesis by degrading tra
nsfer RNA (tRNA) and ribosomal RNA (rRNA), which are essential for translation. SLFN11, for instance, targets tRNAs with a specific sequence, disrupting the production of viral proteins that rely on these tRNAs. This selective degradation effectively hampers the replication of retroviruses like HIV.
-Zinc Finger Antiviral Protein (ZAP): ZAP recognizes and binds to viral RNA sequences, particularly those rich in CpG dinucleotides, marking them for degradation. By binding to these specific RNA sequences, ZAP not only promotes the decay of viral RNA but also inhibits its translation. This dual action significantly reduces the ability of retroviruses to replicate within host cells.
-RNA-activated Protein Kinase (PKR): PKR is another crucial player that gets activated in response to viral infections. It phosphorylates a key protein involved in the initiation of protein synthesis, effectively shutting down the production of both viral and cellular proteins. This broad inhibition helps to contain the spread of the virus during the early stages of infection.
-Shiftless (SFL): SFL targets the translation process of viral mRNAs, particularly those requiring programmed -1 ribosomal frameshifting, a mechanism used by viruses like HIV to synthesize essential proteins. By inhibiting this frameshifting, SFL disrupts the production of viral proteins, thereby reducing the formation of infectious viral particles.
Real-World Implications
This detailed understanding of how ISGs function opens new avenues for therapeutic interventions. For instance, enhancing the activity of these ISGs or mimicking their actions could lead to the development of novel antiviral drugs.
Additionally, understanding the mechanisms of viral resistance against these ISGs can inform strategies to overcome these defenses, making treatments more effective.
-Potential Therapies: Research suggests that manipulating the expression of ISGs like SLFN11 or blocking pathways that viruses use to evade these ISGs could enhance the body's ability to fight infections. For example, boosting SLFN11 levels in certain immune cells might help control HIV replication more effectively, particularly in patients who respond well to antiretroviral therapy.
Overcoming Viral Evasion: Viruses have evolved various strategies to counteract ISGs. HIV, for example, produces proteins that can inhibit PKR or sequester RNA sequences to avoid ZAP targeting. By developing drugs that can inhibit these viral proteins, we could enhance the natural antiviral response of ISGs.
Conclusion
This pioneering research underscores the intricate and powerful ways in which our innate immune system combats viral infections. By harnessing and enhancing the activity of ISGs, we could develop more effective treatments for retroviral infections. As scientists continue to unravel the complexities of these immune responses, the future of antiviral therapy looks promising, offering new hope for those affected by deadly viruses like HIV and HTLV-1.
The study findings were published in the peer reviewed journal: Viruses.
https://www.mdpi.com/1999-4915/16/6/933
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