Nikhil Prasad Fact checked by:Thailand Medical News Team Jun 17, 2025 3 weeks, 4 hours, 38 minutes ago
Thailand Medical News: Scientists from the University of Hong Kong have made an intriguing discovery about SARS-CoV-2, the virus responsible for COVID-19. According to their new study, many dominant variants of the virus have repeatedly lost the ability to secrete a protein called ORF8—despite retaining its genetic sequence. This protein plays key roles in triggering inflammation, evading the immune system, and binding to immune cells like dendritic cells and monocytes.
This
Thailand Medical News report highlights how researchers from the Department of Microbiology and the Centre for Virology, Vaccinology and Therapeutics at the University of Hong Kong, along with the State Key Laboratory for Emerging Infectious Diseases and the AIDS Institute, discovered that ORF8 secretion was absent in multiple SARS-CoV-2 strains including Delta, BA.5.2, Alpha, and the recent XBB.1.5 variant. Even though these strains still encode the ORF8 gene, critical mutations—some without stop codons—disrupt its ability to be secreted, essentially rendering the protein functionally useless.
What Is ORF8 and Why It Matters
ORF8 is a secreted protein unique to SARS-CoV-2 among human coronaviruses. In earlier phases of the pandemic, scientists found that this protein was present in patient blood and even triggered strong antibody responses, hinting at its high immunogenicity. ORF8 was shown to interfere with antigen presentation, contribute to cytokine storms, and even mimic host proteins to confuse the immune system. As such, it has been seen as a multifunctional viral weapon.
However, through cell infection experiments, the Hong Kong research team observed that the secretion of ORF8 had vanished in several major variants, including Delta and BA.5.2. Using virus cultures and Western blot techniques, they showed that while earlier variants like Ancestral, Beta, and Omicron BA.1 and BA.2 still secreted ORF8, others did not.
Key Mutations Behind the ORF8 Secretion Loss
The study identified several mutations responsible for this disruption. These include:
-Q27Stop in the Alpha variant
-G8Stop in XBB.1.5, EG.1.5, and HK.3
-D119-/F120- double deletion in Delta
-C27889U substitution in BA.5.2 and BQ.1.1
While some of these introduce premature stop codons, others do not—meaning standard genome sequencing might overlook the loss of protein function. The C27889U mutation, for instance, occurs upstream in the transcription-regulatory region, yet still results in no ORF8 secretion.
A Roller Coaster Evolution of Gain and Loss
The researchers mapped the evolutionary path of ORF8 through more than 2,000 viral genomes from GISAID, analyzed using Nextstrain and the Augur pipeline. They found that ORF8 secretion was present in the original virus but lost in Alpha and Delta (2021–2022), reappeared in BA.1 and BA.2, then disappeared again in BA.5.2 and XBB.1.5, and has recently re-emerged in JN.1.
This fluct
uating pattern suggests ORF8 is not strictly essential for the virus’s survival but may provide strategic advantages at different points in its evolution. One hypothesis proposed is that ORF8 may function as a “burner” gene—one the virus can afford to deactivate temporarily in order to compensate for other beneficial mutations elsewhere in its genome, such as in the spike protein.
Why This Matters Going Forward
The findings challenge assumptions that a preserved genetic sequence always means a protein is functional. Just because ORF8 exists in a virus’s genome doesn’t mean it’s working. As many functional studies rely solely on genetic sequencing or plasmid models, this discovery underscores the importance of confirming actual protein expression and secretion in live virus infections.
The study also raises concerns about how these recurring mutations could impact the virus’s ability to modulate immune responses. It remains unclear whether the loss of ORF8 secretion contributes to increased or decreased disease severity.
Some studies have shown extracellular ORF8 can drive inflammation, while others suggest it may not significantly alter cytokine profiles. More clinical and immunological research is needed to fully understand these dynamics.
Conclusion
The research demonstrates that the SARS-CoV-2 virus has a recurring pattern of losing and regaining ORF8 secretion ability across various dominant strains. This cyclical behavior suggests a complex evolutionary relationship where the virus may deactivate ORF8 during certain phases to adapt or optimize other functions. While ORF8 is not necessary for viral replication, its immunomodulatory roles make it a key player in how the virus interacts with the human immune system. These findings emphasize the need for researchers to go beyond simple genetic analysis and investigate actual protein functions to understand the virus's evolving strategies.
The study findings were published in the peer reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/26/12/5778
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