ＧＯＵＲＬＡＹ
@gourlaysyd.bsky.social
Accidental Covid nerd. 🇺🇦 Registered Psychologist with Cambridge University Psychology and Theoretical Physics degrees. Xtwitter refugee.
Interesting analysis. Thank you.
(If the Comey case reaches the Supreme Court, this could give SCOTUS a basis for rolling back unfettered presidential immunity … which they probably regret they ever ‘gave’ him in their earlier determination).
(If the Comey case reaches the Supreme Court, this could give SCOTUS a basis for rolling back unfettered presidential immunity … which they probably regret they ever ‘gave’ him in their earlier determination).
November 1, 2025 at 11:36 PM
Interesting analysis. Thank you.
(If the Comey case reaches the Supreme Court, this could give SCOTUS a basis for rolling back unfettered presidential immunity … which they probably regret they ever ‘gave’ him in their earlier determination).
(If the Comey case reaches the Supreme Court, this could give SCOTUS a basis for rolling back unfettered presidential immunity … which they probably regret they ever ‘gave’ him in their earlier determination).
Different HLAs? So you're arguing that the reinfected RI group comprises people with less protective HLA alleles ie B*46:01, C*01:02?
If true this alone would be cause for concern, that a significant population is prone to repeated infection (and concomitant persistent multi-organ dysfunction).
If true this alone would be cause for concern, that a significant population is prone to repeated infection (and concomitant persistent multi-organ dysfunction).
November 1, 2025 at 11:20 PM
Different HLAs? So you're arguing that the reinfected RI group comprises people with less protective HLA alleles ie B*46:01, C*01:02?
If true this alone would be cause for concern, that a significant population is prone to repeated infection (and concomitant persistent multi-organ dysfunction).
If true this alone would be cause for concern, that a significant population is prone to repeated infection (and concomitant persistent multi-organ dysfunction).
Yep. I’m surprised you’re not familiar with them. The most variable part of the TCR and underlies broad protective T-cell immunity
SARS-CoV-2-specific CDR3α & CDR3β amino acid sequences from the VDJdb database (a curated repository of experimentally validated T-cell receptor-antigen interactions)
SARS-CoV-2-specific CDR3α & CDR3β amino acid sequences from the VDJdb database (a curated repository of experimentally validated T-cell receptor-antigen interactions)
October 30, 2025 at 10:19 AM
Yep. I’m surprised you’re not familiar with them. The most variable part of the TCR and underlies broad protective T-cell immunity
SARS-CoV-2-specific CDR3α & CDR3β amino acid sequences from the VDJdb database (a curated repository of experimentally validated T-cell receptor-antigen interactions)
SARS-CoV-2-specific CDR3α & CDR3β amino acid sequences from the VDJdb database (a curated repository of experimentally validated T-cell receptor-antigen interactions)
HC = protective T-cell repertoire
RI is missing many SARS-CoV-2-specific TCR V(D)J combinations (cf HC) that SHOULD exist (both HC & RI infected in China’s first wave in December 2022 wave)
RI is missing many SARS-CoV-2-specific CDR3 motifs.
➝ RI is not retaining broad, protective T-cell memory
RI is missing many SARS-CoV-2-specific TCR V(D)J combinations (cf HC) that SHOULD exist (both HC & RI infected in China’s first wave in December 2022 wave)
RI is missing many SARS-CoV-2-specific CDR3 motifs.
➝ RI is not retaining broad, protective T-cell memory
October 30, 2025 at 9:31 AM
HC = protective T-cell repertoire
RI is missing many SARS-CoV-2-specific TCR V(D)J combinations (cf HC) that SHOULD exist (both HC & RI infected in China’s first wave in December 2022 wave)
RI is missing many SARS-CoV-2-specific CDR3 motifs.
➝ RI is not retaining broad, protective T-cell memory
RI is missing many SARS-CoV-2-specific TCR V(D)J combinations (cf HC) that SHOULD exist (both HC & RI infected in China’s first wave in December 2022 wave)
RI is missing many SARS-CoV-2-specific CDR3 motifs.
➝ RI is not retaining broad, protective T-cell memory
Yes, those reinfected (RI):
▷ have fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
▷ lack protective CDR3 motifs: RI=3070 vs HC=3321
Their T-cell landscape fails to retain broad, protective T-cell memory
This isn’t “normal” ❌
▷ have fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
▷ lack protective CDR3 motifs: RI=3070 vs HC=3321
Their T-cell landscape fails to retain broad, protective T-cell memory
This isn’t “normal” ❌
October 30, 2025 at 7:20 AM
Yes, those reinfected (RI):
▷ have fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
▷ lack protective CDR3 motifs: RI=3070 vs HC=3321
Their T-cell landscape fails to retain broad, protective T-cell memory
This isn’t “normal” ❌
▷ have fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
▷ lack protective CDR3 motifs: RI=3070 vs HC=3321
Their T-cell landscape fails to retain broad, protective T-cell memory
This isn’t “normal” ❌
The reinfected RI group
* share fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
* lack protective CDR3 motifs: RI=3070 vs HC=3321
Their TCR landscape is a failure to retain broad, protective T-cell memory
This isn’t “normal” ❌
2/2
* share fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
* lack protective CDR3 motifs: RI=3070 vs HC=3321
Their TCR landscape is a failure to retain broad, protective T-cell memory
This isn’t “normal” ❌
2/2
October 30, 2025 at 7:14 AM
The reinfected RI group
* share fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
* lack protective CDR3 motifs: RI=3070 vs HC=3321
Their TCR landscape is a failure to retain broad, protective T-cell memory
This isn’t “normal” ❌
2/2
* share fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
* lack protective CDR3 motifs: RI=3070 vs HC=3321
Their TCR landscape is a failure to retain broad, protective T-cell memory
This isn’t “normal” ❌
2/2
Thank you, I take your point, there’s no sign of persistent dysfunction in the healthy convalescent (HC) group at 9 months (T-cells have adapted appropriately). ✅
BUT in the reinfected RI group T-cell memory failed to mature into the HC protective state. That’s the issue.
1/2
BUT in the reinfected RI group T-cell memory failed to mature into the HC protective state. That’s the issue.
1/2
October 30, 2025 at 7:14 AM
Thank you, I take your point, there’s no sign of persistent dysfunction in the healthy convalescent (HC) group at 9 months (T-cells have adapted appropriately). ✅
BUT in the reinfected RI group T-cell memory failed to mature into the HC protective state. That’s the issue.
1/2
BUT in the reinfected RI group T-cell memory failed to mature into the HC protective state. That’s the issue.
1/2
Unfortunately, I don’t think you know what you are talking about. Even Prof Veldhoen sees an effect, but he argues this is a natural “learning” by the immune system. The debate is around whether SC2 in addition narrows immune flexibility and therefore response to novel pathogens.
October 29, 2025 at 1:46 AM
Unfortunately, I don’t think you know what you are talking about. Even Prof Veldhoen sees an effect, but he argues this is a natural “learning” by the immune system. The debate is around whether SC2 in addition narrows immune flexibility and therefore response to novel pathogens.
… in determining V(D)J bias the Frontiers authors explicitly note that “reference repertoires from healthy donors” were used for baseline comparison. These are drawn from public pre-pandemic databases of uninfected individuals (not their own cohort).
There’s your healthy ‘controls’ for comparison.
There’s your healthy ‘controls’ for comparison.
October 28, 2025 at 11:22 PM
… in determining V(D)J bias the Frontiers authors explicitly note that “reference repertoires from healthy donors” were used for baseline comparison. These are drawn from public pre-pandemic databases of uninfected individuals (not their own cohort).
There’s your healthy ‘controls’ for comparison.
There’s your healthy ‘controls’ for comparison.
‘Biased’ V(D)J usage is by definition wrt a naive (uninfected) population. The HC group at 9 months showed skewed V(D)J usage. By definition this reduces diversity in the TCR repertoire … some patterns will be missing, unavailable for recognition & clonal expansion
cf a naive (not infected) group.
cf a naive (not infected) group.
October 28, 2025 at 10:57 PM
‘Biased’ V(D)J usage is by definition wrt a naive (uninfected) population. The HC group at 9 months showed skewed V(D)J usage. By definition this reduces diversity in the TCR repertoire … some patterns will be missing, unavailable for recognition & clonal expansion
cf a naive (not infected) group.
cf a naive (not infected) group.
By definition in non-infected groups there is no V(D)J segment bias (by definition) … but we see this in the Healthy Convalescent HC group at >9 months.
October 28, 2025 at 1:04 PM
By definition in non-infected groups there is no V(D)J segment bias (by definition) … but we see this in the Healthy Convalescent HC group at >9 months.
The HC group is measured at >9 months from infection. Hence, persistent skewing [V(D)J segment bias, especially TRAV35/TRAJ42].
October 28, 2025 at 12:51 PM
The HC group is measured at >9 months from infection. Hence, persistent skewing [V(D)J segment bias, especially TRAV35/TRAJ42].
Show me a reference for another disease that you:
(a) get once every 1-2 years (at least) and (b) has the same impact on T cells.
(a) get once every 1-2 years (at least) and (b) has the same impact on T cells.
October 28, 2025 at 12:34 PM
Show me a reference for another disease that you:
(a) get once every 1-2 years (at least) and (b) has the same impact on T cells.
(a) get once every 1-2 years (at least) and (b) has the same impact on T cells.
Healthy Convalescents (HC) were analysed 9 months post infection and showed clear V(D)J segment bias, especially TRAV35/TRAJ42, indicating persistent (>9 months) repertoire skewing (non-infected people would not show this skewing).
October 28, 2025 at 12:32 PM
Healthy Convalescents (HC) were analysed 9 months post infection and showed clear V(D)J segment bias, especially TRAV35/TRAJ42, indicating persistent (>9 months) repertoire skewing (non-infected people would not show this skewing).
Yes, there is another infection where there is loss of TCR diversity (severe & progressive) and skewed V(D)J usage (persistent): HIV ➝ AIDS
So you are right, similar effects are seen in another infectious disease: HIV/AIDS
So you are right, similar effects are seen in another infectious disease: HIV/AIDS
October 28, 2025 at 10:16 AM
Yes, there is another infection where there is loss of TCR diversity (severe & progressive) and skewed V(D)J usage (persistent): HIV ➝ AIDS
So you are right, similar effects are seen in another infectious disease: HIV/AIDS
So you are right, similar effects are seen in another infectious disease: HIV/AIDS
2/2 After 9 months the TCR diversity in HC (convalescent) group is higher than in acute infection (some recovery), but LOWER than uninfected controls and also skewed, with biased V(D)J usage.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent remodelling.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent remodelling.
October 28, 2025 at 9:59 AM
2/2 After 9 months the TCR diversity in HC (convalescent) group is higher than in acute infection (some recovery), but LOWER than uninfected controls and also skewed, with biased V(D)J usage.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent remodelling.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent remodelling.
1/2
After 9 months the TCR diversity in HC (convalescent) group is higher than in acute infection (some recovery), but LOWER than uninfected controls and also skewed, with biased V(D)J usage.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent.
After 9 months the TCR diversity in HC (convalescent) group is higher than in acute infection (some recovery), but LOWER than uninfected controls and also skewed, with biased V(D)J usage.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent.
October 28, 2025 at 9:57 AM
1/2
After 9 months the TCR diversity in HC (convalescent) group is higher than in acute infection (some recovery), but LOWER than uninfected controls and also skewed, with biased V(D)J usage.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent.
After 9 months the TCR diversity in HC (convalescent) group is higher than in acute infection (some recovery), but LOWER than uninfected controls and also skewed, with biased V(D)J usage.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent.
The immune system’s available T-cell pool is reallocated, inappropriately skewed toward antigenic specificities.
Persistent remodelling will inevitably carry a functional cost (even if not yet directly demonstrated) by narrowing the diversity of T-cells available to respond to unfamiliar pathogens.
Persistent remodelling will inevitably carry a functional cost (even if not yet directly demonstrated) by narrowing the diversity of T-cells available to respond to unfamiliar pathogens.
October 28, 2025 at 8:02 AM
The immune system’s available T-cell pool is reallocated, inappropriately skewed toward antigenic specificities.
Persistent remodelling will inevitably carry a functional cost (even if not yet directly demonstrated) by narrowing the diversity of T-cells available to respond to unfamiliar pathogens.
Persistent remodelling will inevitably carry a functional cost (even if not yet directly demonstrated) by narrowing the diversity of T-cells available to respond to unfamiliar pathogens.
Dysfunction ≠ lymphopenia
Frontiers doesn’t claim that SARS-CoV-2 kills T-cells or causes lymphopenia. It finds significant skewing in TCR repertoire diversity after recovery & reinfection that is unusually *persistent* for an acute infection
reducing flexibility to respond to novel pathogens.
Frontiers doesn’t claim that SARS-CoV-2 kills T-cells or causes lymphopenia. It finds significant skewing in TCR repertoire diversity after recovery & reinfection that is unusually *persistent* for an acute infection
reducing flexibility to respond to novel pathogens.
October 28, 2025 at 7:38 AM
Dysfunction ≠ lymphopenia
Frontiers doesn’t claim that SARS-CoV-2 kills T-cells or causes lymphopenia. It finds significant skewing in TCR repertoire diversity after recovery & reinfection that is unusually *persistent* for an acute infection
reducing flexibility to respond to novel pathogens.
Frontiers doesn’t claim that SARS-CoV-2 kills T-cells or causes lymphopenia. It finds significant skewing in TCR repertoire diversity after recovery & reinfection that is unusually *persistent* for an acute infection
reducing flexibility to respond to novel pathogens.
So this is a cumulative immune remodelling (not “nothing to see here”) and a progressive narrowing of adaptive options with fewer unique TCRs to meet the next novel pathogen.
Repeated COVID infections leave us less equipped to deal with novel pathogens.
That’s WHY we’re getting sicker more often.
Repeated COVID infections leave us less equipped to deal with novel pathogens.
That’s WHY we’re getting sicker more often.
October 28, 2025 at 5:01 AM
So this is a cumulative immune remodelling (not “nothing to see here”) and a progressive narrowing of adaptive options with fewer unique TCRs to meet the next novel pathogen.
Repeated COVID infections leave us less equipped to deal with novel pathogens.
That’s WHY we’re getting sicker more often.
Repeated COVID infections leave us less equipped to deal with novel pathogens.
That’s WHY we’re getting sicker more often.
Reposted by ＧＯＵＲＬＡＹ
WRONG
You:
1) Confuse transient repertoire contraction with normal clonal expansion
2) Wrongly assume no lymphopenia = no immunological dysfunction
3) Claim the Frontiers paper shows normal memory formation. No, it is evidence of cumulative immune remodelling (persistent, skewed changes)
etc
You:
1) Confuse transient repertoire contraction with normal clonal expansion
2) Wrongly assume no lymphopenia = no immunological dysfunction
3) Claim the Frontiers paper shows normal memory formation. No, it is evidence of cumulative immune remodelling (persistent, skewed changes)
etc
October 28, 2025 at 2:41 AM
WRONG
You:
1) Confuse transient repertoire contraction with normal clonal expansion
2) Wrongly assume no lymphopenia = no immunological dysfunction
3) Claim the Frontiers paper shows normal memory formation. No, it is evidence of cumulative immune remodelling (persistent, skewed changes)
etc
You:
1) Confuse transient repertoire contraction with normal clonal expansion
2) Wrongly assume no lymphopenia = no immunological dysfunction
3) Claim the Frontiers paper shows normal memory formation. No, it is evidence of cumulative immune remodelling (persistent, skewed changes)
etc
ie 3) There’s persistent changes in TCR repertoire diversity after reinfection. T-cell memory responses differ qualitatively (biased VDJ usage, distinct clonotypes) suggesting functional reshaping of the T-cell pool after repeated SC2 infections
That is not “no effect”. It’s cumulative remodelling.
That is not “no effect”. It’s cumulative remodelling.
October 28, 2025 at 3:42 AM
ie 3) There’s persistent changes in TCR repertoire diversity after reinfection. T-cell memory responses differ qualitatively (biased VDJ usage, distinct clonotypes) suggesting functional reshaping of the T-cell pool after repeated SC2 infections
That is not “no effect”. It’s cumulative remodelling.
That is not “no effect”. It’s cumulative remodelling.
i.e.
2) Absence of gross lymphopenia does not rule out phenotypic exhaustion, altered subset ratios, or defective proliferative potential. The Frontiers data (especially TCRβ diversity and CDR3 usage) suggest selective repertoire narrowing, even without overall cell loss.
2) Absence of gross lymphopenia does not rule out phenotypic exhaustion, altered subset ratios, or defective proliferative potential. The Frontiers data (especially TCRβ diversity and CDR3 usage) suggest selective repertoire narrowing, even without overall cell loss.
October 28, 2025 at 3:34 AM
i.e.
2) Absence of gross lymphopenia does not rule out phenotypic exhaustion, altered subset ratios, or defective proliferative potential. The Frontiers data (especially TCRβ diversity and CDR3 usage) suggest selective repertoire narrowing, even without overall cell loss.
2) Absence of gross lymphopenia does not rule out phenotypic exhaustion, altered subset ratios, or defective proliferative potential. The Frontiers data (especially TCRβ diversity and CDR3 usage) suggest selective repertoire narrowing, even without overall cell loss.