Long COVID & viral persistence - new evidence
A new study detected a peptide fragment specific to SARS-CoV-2 nsp3 in blood extracellular vesicles (EVs) from Long COVID patients - months to years after infection.
Let’s unpack why this matters.🧵
A new study detected a peptide fragment specific to SARS-CoV-2 nsp3 in blood extracellular vesicles (EVs) from Long COVID patients - months to years after infection.
Let’s unpack why this matters.🧵
EVs are tiny membrane packages released by cells, carrying proteins, RNA, and lipids.
They can travel in blood, cross biological barriers, and deliver their contents to other cells - bypassing normal immune surveillance!
They can travel in blood, cross biological barriers, and deliver their contents to other cells - bypassing normal immune surveillance!
The detected peptide - GSLPINVIVFDGK - is uniquely part of nsp3, a large viral enzyme encoded by ORF1ab.
Nsp3 is crucial for SARS-CoV-2 replication and immune evasion.
Importantly - the study found the peptide, not necessarily the entire intact protein.
Nsp3 is crucial for SARS-CoV-2 replication and immune evasion.
Importantly - the study found the peptide, not necessarily the entire intact protein.
This nuance matters:
If it’s just a fragment, it might be biologically inert.
If it contains active domains, it could still disrupt host cell processes.
We don’t know which scenario applies here - but either way, it’s proof of viral material in long Covid circulation.
If it’s just a fragment, it might be biologically inert.
If it contains active domains, it could still disrupt host cell processes.
We don’t know which scenario applies here - but either way, it’s proof of viral material in long Covid circulation.
Results:
12/14 Long COVID patients had this nsp3-specific peptide in at least one blood sample (across 4 time points).
None of the recovered COVID patients or uninfected controls tested positive.
12/14 Long COVID patients had this nsp3-specific peptide in at least one blood sample (across 4 time points).
None of the recovered COVID patients or uninfected controls tested positive.
The study only sampled during exercise testing.
Exercise can mobilize proteins and debris from tissues - think of it as shaking a snow globe.
So this may reflect what’s shaken loose from reservoirs, not constant circulation.
Exercise can mobilize proteins and debris from tissues - think of it as shaking a snow globe.
So this may reflect what’s shaken loose from reservoirs, not constant circulation.
Context: Nsp3 is a multifunctional protein that:
Remodels the endoplasmic reticulum (ER) into a viral factory
Hijacks lipid metabolism to fuel replication
Interferes with mitochondrial function
Modulates innate immunity to help the virus persist
Remodels the endoplasmic reticulum (ER) into a viral factory
Hijacks lipid metabolism to fuel replication
Interferes with mitochondrial function
Modulates innate immunity to help the virus persist
How SARS-CoV-2 turns a cell into its factory (second study):
NSP3, NSP4, NSP6 - remodel the endoplasmic reticulum (ER) into protected replication zones.
ORF8, NSP4 - hijack ER stress responses to favor the virus.
ORF3a, ORF7a - exploit autophagy, rerouting waste away from lysosomes so the cell can’t clean itself.
Damages mitochondria to weaken immunity.
Forces the cell to make extra lipids (ceramides, phosphatidic acids) for building materials and energy.
End result: a protected viral factory, an overloaded cell, damaged tissue. pubmed.ncbi.nlm.nih.gov/40295886/
NSP3, NSP4, NSP6 - remodel the endoplasmic reticulum (ER) into protected replication zones.
ORF8, NSP4 - hijack ER stress responses to favor the virus.
ORF3a, ORF7a - exploit autophagy, rerouting waste away from lysosomes so the cell can’t clean itself.
Damages mitochondria to weaken immunity.
Forces the cell to make extra lipids (ceramides, phosphatidic acids) for building materials and energy.
End result: a protected viral factory, an overloaded cell, damaged tissue. pubmed.ncbi.nlm.nih.gov/40295886/
Persistent nsp3 in EVs could maintain neuroinflammation, disrupt glial communication, and worsen cognitive symptoms (brain fog).
Mitochondria: nsp3 impacts the cell’s energy hubs, contributing to fatigue and post-exertional malaise (PEM).
Mitochondria: nsp3 impacts the cell’s energy hubs, contributing to fatigue and post-exertional malaise (PEM).
Viral proteins packaged in EVs can bypass immune surveillance, reprogram cell metabolism, and impact the nervous system - even without active viral replication.
This is a well-documented feature in HIV, and SARS-CoV-2 appears to exploit a similar strategy.
This is a well-documented feature in HIV, and SARS-CoV-2 appears to exploit a similar strategy.
Abbasi et al.s work offers a potential biomarker for #LongCOVID (nsp3 in EVs), but also a warning: persistent viral proteins may be active drivers of long-term symptoms - not just leftovers from infection.
Context from other research - another ORF1ab enzyme - Mpro (nsp5, the main protease) - can cleave TDP-43, a key protein for neuron health.
TDP-43 damage is linked to ALS and dementia.
If Mpro ever circulated like nsp3 fragments do here, it could pose a direct neurodegenerative risk.
TDP-43 damage is linked to ALS and dementia.
If Mpro ever circulated like nsp3 fragments do here, it could pose a direct neurodegenerative risk.
Bottom line.
Detection of an nsp3-derived peptide in EVs months–years post-infection is strong evidence of ongoing viral material in the body.
Whether it’s harmless debris or an active weapon depends on the fragment’s function - and we urgently need to find out.
Detection of an nsp3-derived peptide in EVs months–years post-infection is strong evidence of ongoing viral material in the body.
Whether it’s harmless debris or an active weapon depends on the fragment’s function - and we urgently need to find out.
Abbasi et al. (2025). Possible long COVID biomarker: identification of SARS‑CoV‑2 related protein(s) in Serum Extracellular Vesicles. Infection, 2025 ?link.springer.com/article/10.100…
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