Review paper.
At the center of Long COVID are three processes that reinforce each other -
persistent viral material, damage to the gut barrier, and chronic immune dysregulation. Together, they help explain why neurological and neuropsychiatric symptoms are so common and so persistent🧵
Viral persistence.
In a subset of people, fragments of SARS-CoV-2 - especially spike protein - persist for months or even years after the acute infection.
These viral remnants don’t need to actively replicate. Their continued presence is enough to keep the immune system switched on, similar to what we see in chronic viral infections like HIV.
The gut is a key driver.
SARS-CoV-2 infects intestinal epithelial cells, where ACE2 is highly expressed.
This leads to persistent gut dysbiosis, breakdown of epithelial tight junctions, and altered IgA/IgG coating of commensal bacteria - a clear sign of disrupted mucosal immune control.
As the gut barrier weakens, microbial products such as lipopolysaccharide (LPS) and β-glucan leak into the bloodstream.
This microbial translocation continuously stimulates innate immune receptors and sustains systemic inflammation.
Chronic innate immune activation.
In Long COVID, myeloid cells and neutrophils remain chronically activated.
There is ongoing formation of neutrophil extracellular traps (NETs), which promotes immunothrombosis, microclot formation, and micro-hypoxia.
This impairs microvascular perfusion across organs and creates a self-reinforcing inflammatory loop.
Gut - blood - immune system - tissue injury.
Adaptive immunity is dysregulated.
The adaptive immune system shows signs of poor coordination between T- and B- cells, functional exhaustion, and increased autoreactivity.
These patterns resemble immunosenescence and chronic viral immune imprinting, where persistent antigen exposure gradually erodes immune balance rather than restoring it.
Barrier failure reaches the brain.
Systemic inflammation does not stay in the periphery.
Cytokines, microbial products, fibrin, and persistent viral antigens disrupt the blood–brain barrier (BBB).
Once the BBB is compromised, inflammatory signals and activated immune cells gain access to the central nervous system.
Neuroinflammation explains the symptoms.
Within the brain, activation of microglia and astrocytes provides a biological explanation for hallmark symptoms of Long COVID -
brain fog, cognitive slowing, fatigue, mood disturbances, and dysautonomia.
Crucially, widespread or productive infection of the brain is not required.
The combination of systemic inflammation, vascular dysfunction, and barrier failure is sufficient to drive neuroinflammation.
Parallels with other post-infectious conditions.
The authors explicitly compare Long COVID with conditions such as chronic HIV infection, post-Ebola syndrome, post-Lyme disease syndrome, and ME/CFS.
Across all of these, similar patterns emerge -
persistent pathogen-derived material, gut barrier dysfunction, chronic innate immune activation, blood–brain barrier disruption, and long-term neurological consequences.
What this means?
Long COVID should be understood as a biological disorder of immune regulation and barrier integrity.
Effective treatment will likely require combination approaches, aimed at reducing antigen load, restoring gut barrier function, and calming dysregulated immune and coagulation pathways - rather than focusing on symptoms alone.
Sum:
Long COVID emerges when lingering viral antigens, a damaged gut barrier, and a chronically overactivated immune system converge to disrupt blood vessels, protective barriers, and the brain.
Leclerc at al., Intestinal barrier compromise, viral persistence, and immune dysregulation converge on neurological sequelae in Long COVID. frontiersin.org/journals/aging…
It’s not surprising that the authors frame Long COVID as HIV-like.
The mechanisms they describe are HIV-like by nature, not by analogy.
These are core features of chronic HIV infection, extensively described long before COVID.
The difference is not the biology - it’s the virus.
HIV integrates and persists as a retrovirus.
SARS-CoV-2 persists through antigen reservoirs, tissue sanctuaries, and immune evasion, but the downstream immune pathology converges on the same pathways.
That’s why parallels with HIV are not speculative.
They are mechanistically justified.
And that’s also why ignoring Long COVID - or framing it as psychosomatic - repeats mistakes already made in early HIV research.
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