Thread by @ZdenekVrozina

What connects HIV and SARS-CoV-2 in the brain?
Not structural homology - but functional parallels between viral proteins that can drive chronic neuroinflammation and immune evasion.
A short thread on Tat, viroporins, ORF8, and viral neuropathogenesis. @dbdugger 🧵

COVID-19 (Long COVID) is associated with:
microglial activation
blood-brain barrier (BBB) disruption
persistent viral antigens
memory and attention deficits
These are also key features of HIV-associated neurocognitive disorder (HAND). What’s the link?

In HIV, the Tat protein is central to neuropathology:
secreted from infected cells
crosses the BBB
activates microglia via TLR4
triggers IL-6, TNFa, ROS
promotes excitotoxicity in neurons
Tat = neurotoxic transcriptional regulator.

SARS-CoV-2 doesn’t have Tat.
But several of its proteins show comparable effects on inflammatory and neuroimmune pathways, especially:
viroporin E (inflammasome activation)
ORF8 (MHC-I downregulation)
Spike S1 (BBB disruption, NRP1 binding)

Viroporin E:
small transmembrane viral protein
forms ion channels !
activates NLRP3 inflammasome via K+ efflux
leads to IL-1β release, pyroptosis
Functionally similar to HIV Tat, which induces calcium influx, oxidative stress and inflammation. (Popa et al. 2025) mdpi.com/1422-0067/26/1…

Virology 2022. Demonstrates that SARS‑CoV‑2 viroporins (E and ORF3a) directly activate the NLRP3 inflammasome. pubmed.ncbi.nlm.nih.gov/35066302/

Another parallel:
HIV gp120 - SARS-CoV-2 Spike S1
both are viral envelope glycoproteins
bind host cell receptors (CD4/CCR5 vs. ACE2/NRP1)
can disrupt the BBB
activate microglia and cytokine release.
(Paniz-Mondolfi et al., Nat Neurosci 2020) pubmed.ncbi.nlm.nih.gov/32314810/

Immune evasion:
HIV uses Nef to downregulate MHC-I, helping infected cells evade CD8+ T cells.
SARS-CoV-2 uses ORF8, which:
binds MHC-I
retains it in the ER
promotes lysosomal degradation
impairs antigen presentation.
(Zhang et al. (2021) on ORF8 and MHC‑I) pubmed.ncbi.nlm.nih.gov/34021074/

Complementary role - SARS-CoV-2 ORF6 suppresses STAT1-IRF1-NLRC5, blocking MHC-I transcription and antigen processing. pubmed.ncbi.nlm.nih.gov/34782627/

Now Popa et al., IJMS 2025 (Narrative Review):
highlights spike and E protein in NLRP3 activation
shows overlap in transcriptomic response with Alzheimer’s
reports evidence for BBB impairment and energy metabolism disruption mdpi.com/1422-0067/26/1…

HIV Tat and SC2 Viroporin E
inflammasome activation, neuroinflammation
HIV gp120 and SC2 Spike S1
receptor binding, BBB disruption
HIV Nef and SC2 ORF8/ORF6
MHC-I downregulation, immune evasion
These are functional analogies - not homologous proteins.

Persistent symptoms may not stem from viral replication - but from viral proteins that remain detectable by the immune system while resisting clearance, especially in tissues like CNS, gut, and lymphoid organs. nature.com/articles/s4157…

SARS-CoV-2 is not HIV.
But some of its proteins - like viroporin E, ORF8, and spike - exhibit functional similarities to Tat, Nef, and gp120.

These parallels may help explain why symptoms persist in some individuals even after viral clearance:
Not because of active replication, but due to persistent viral proteins that remain visible to the immune system, yet are difficult to eliminate.
HIV has taught us that immune evasion and protein persistence can last for decades.
Whether we'll manage better this time... remains to be seen.