![Page 1: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/1.jpg)
The role of immune responses in HIV-1 Infection
Marylyn M. Addo, MD/PhD
Partners AIDS Research Center
Massachusetts General Hospital
Harvard Medical School
Boston, MA USA
![Page 2: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/2.jpg)
Altfeld_CAP150_03
1000
800
600
400
200
1 5 10Time (years)Time (years)
CD
4 p
er m
mC
D4
per
mm
33
Natural History of HIV-1
VZVVZV
TBTB
Kaposi SarcomaKaposi Sarcoma
PCPPCP
15
CMV MAC Crypto LymphomaCMV MAC Crypto Lymphoma
symptomssymptoms
CD4CD4
HIV RNAHIV RNA
HIV
RN
A c
op
ies/
ml
HIV
RN
A c
op
ies/
ml
104
105
106
![Page 3: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/3.jpg)
The level of HIV in the blood stream predicts subsequent survival
RN
A p
arti
cles
/ml
pla
sma
One year
Rapid Progression
Slow Progression
Viral set point
![Page 4: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/4.jpg)
What influences viral load in HIV infection?
![Page 5: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/5.jpg)
Viruses are not able to reproduce on their own
![Page 6: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/6.jpg)
New virusassembly
2-3 Days
![Page 7: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/7.jpg)
Viral set point is determined
by number of viruses produced by infected cells
![Page 8: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/8.jpg)
Potential factors influencing the viral set
pointAttenuated virus
Host genetic factors
Host immuneresponse
![Page 9: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/9.jpg)
Potential factors influencing the viral set
pointAttenuated virus
Host genetic factors
Host immuneresponse
HAARTHAART
![Page 10: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/10.jpg)
New virusassembly
2-3 Days
Attenuated viruses
Example: Sidney blood bank cohortExample: Sidney blood bank cohort
Virus had a “mistake” in the nef geneVirus had a “mistake” in the nef gene
![Page 11: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/11.jpg)
Attenuated viruses
Host genetic factors
![Page 12: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/12.jpg)
CD4 CCR5
Co-receptor polymorphisms can prevent entry of virus into cells
32 base pair deletion in CCR5
![Page 13: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/13.jpg)
B27 B57
Migueles, PNAS 97:2709, 2000
Some molecules on the cell of an individual are associated Some molecules on the cell of an individual are associated with improved viral control and slow disease progressionwith improved viral control and slow disease progression
![Page 14: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/14.jpg)
Attenuated viruses
Host immune responses
Host genetic factors
![Page 15: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/15.jpg)
New virusassembly
Humoral Immune System: Neutralizing Antibodies
B cell
![Page 16: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/16.jpg)
New virusassembly
CTL
Solublefactors
Cellular immune Cellular immune system:system:
Killer T cellsKiller T cells
Cytotoxic T cellCytotoxic T cell
![Page 17: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/17.jpg)
New virusassembly
CTL
Solublefactors
B cell
Th
Th
![Page 18: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/18.jpg)
B cell
Th
Th
CTL
![Page 19: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/19.jpg)
The Generals(T helper cells trained to target HIV)
![Page 20: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/20.jpg)
Generals(T Helper cells)
Infantry(CTL)
EnemyInfected cell
![Page 21: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/21.jpg)
Why are the generals absent in most infected persons?
![Page 22: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/22.jpg)
Generals(T Helper cells)
Infantry(CTL)
EnemyInfected cell
![Page 23: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/23.jpg)
Virus-Specific T Helper Cells:Essential for Maintenance of Effective CTL
Th cells absent Th cells present
Rel
ativ
e m
agn
itu
de
CTLViremia
ViremiaCTL
![Page 24: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/24.jpg)
Is there any way to enhance the immune response against HIV?
![Page 25: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/25.jpg)
Generals(T helper cells)
Infantry(CTL)
Enemy(Infected cells)
![Page 26: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/26.jpg)
HAART
Generals(T Helper cells)
Infantry(CTL)
Enemy(Infected cell)
![Page 27: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/27.jpg)
1
10
100
1000
0 20 40 60 80Ma
gn
itu
de
of
He
lpe
r C
ells
Effect of Early Treatment on the Generals
(HIV-Specific T Helper Cells)
Weeks on Treatment
![Page 28: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/28.jpg)
What happens if you stop treatment?
![Page 29: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/29.jpg)
0
40000
80000
120000
160000
0 5 10 15 20 25 30 35 40
Weeks after first treatment interruption
vira
l lo
ad (
cop
ies
RN
A/m
L)
HAART
Early treatment of acute HIV infectionfollowed by treatment interruption
![Page 30: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/30.jpg)
Very early treatment with HAART leads to enhanced natural control
of HIV
![Page 31: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/31.jpg)
Where else do we find evidence for immune control in AIDS virus infection ?
In monkey studies, removing killer cells led to dramatic increases in viral load and restoring Killer T cells in those same monkey studies led to suppression of viral load
Individuals with high levels of Killer T cells have been shown to have low viral loads
Two interesting groups of individuals— HIV-1 long-term nonprogressors (LTNP)— HIV-1 exposed, but uninfected individuals (HEPS)
![Page 32: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/32.jpg)
• Infected 21 years• Normal T cells• Undetectable viral load• Never on anti-HIV meds
LTNP
LTNP have strong and broadly directed killer cell responses and helper cell responses
![Page 33: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/33.jpg)
HEPS Most well known:
— Nairobi sex worker cohort (Rowland-Jones et al.)
— Found killer T cell responses in these HEPS, that may contribute to protection from HIV
— Our group: collaboration with Lusaka, Zambia (PI: Susan Allen) studying killer cells in discordant couples and their partners
Poster session Poster session Thursday 12-2 pm (Addo)Thursday 12-2 pm (Addo)
![Page 34: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/34.jpg)
Vaccine development Based on these pieces of data, it is felt that an
effective HIV-1 vaccine needs to elicit cellular
immune responses, in particular Killer T cell
responses +/- Helper T cell responses
Most recent and compelling data derive from
monkey studies demonstrating that Killer T
cell have an impact on vaccine efficacy in this
setting (Robbinson, Barouch/Letvin, Shiver)
Many vaccine approaches/trials currently in
study
![Page 35: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/35.jpg)
Our current Research
Understanding of total the killer T cell and helper cell response against HIV, not only to single proteins like previous studies.
Analysis of the virus by sequencing
Bruce Walker morning Tuesday plenaryBruce Walker morning Tuesday plenary
Addo A05 Tuesday 14-15:30Addo A05 Tuesday 14-15:30
![Page 36: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/36.jpg)
More research needed for other virus types and other ethnicities
Durban, RSA
Immune responses in Clade
C-Infection
Mother to child transmission
and pediatric treatment and
treatment interruption
studies
NIH contract Epitope
mapping in Non-Caucasians
![Page 37: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/37.jpg)
Nelson Mandela School of MedicineUniversity of Natal
Lab
![Page 38: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/38.jpg)
Why is HIV not controlled by the immune system like
other chronic viral infections?
Mono
Chicken pox
Herpes simplex
![Page 39: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/39.jpg)
Problems
VIRAL ESCAPE
VIRAL DIVERSITY
![Page 40: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/40.jpg)
How HIV mutates to escape Killer T-cells
![Page 41: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/41.jpg)
Examples: Goulder et al, Nature 2001
— Viral escape mutants can be transmitted from mother to child
Barouch et al, Nature 2002— Loss of viral control in a vaccinated animal
associated with viral escape in one epitope
Viral escape
![Page 42: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/42.jpg)
Viral DiversityComparing Viruses:
How much does HIV evolve compared to Flu?
Less Variation More Variation
![Page 43: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/43.jpg)
Influenza variationcompared to HIV variation
1997-1998 Canadian Flu
1996 Global Flu
![Page 44: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/44.jpg)
Influenza variationcompared to HIV variation
1990-1991Amsterdam
1997Dem Rep of Congo
1997-1998 Canadian Flu
1996 Global Flu
![Page 45: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/45.jpg)
The extreme variability of HIV over time is a major impediment to immune control, effective drug therapy and vaccine development
![Page 46: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/46.jpg)
![Page 47: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/47.jpg)
![Page 48: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/48.jpg)
Acknowledgements Marcus AltfeldMarcus Altfeld
Xu Yu Xu Yu
Almas RathodAlmas Rathod
Cecily FitzpatrickCecily Fitzpatrick
Paul LeePaul Lee
Philip GoulderPhilip Goulder
Christian BranderChristian Brander
Eric RosenbergEric Rosenberg
Bruce WalkerBruce Walker
Funding Sources:Funding Sources:
German Research Council (DFG)German Research Council (DFG)
amfARamfAR
Concerned Parents for AIDS Research (CPFA)Concerned Parents for AIDS Research (CPFA)
![Page 49: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/49.jpg)
102
103
104
105
106
HLA-B27 is associated with slow progression to AIDS
ViralLoad
n = 10 HLA-B27+
![Page 50: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/50.jpg)
HLA B27 molecule
I
W
K
I L
K
GL
The dominant CTL response in HLA-B27+ individuals:HIV Gag p24 KK10 epitope
LR
![Page 51: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/51.jpg)
B27-KK10 escape is associated with elevated viral load
Non-controllers
p=0.025
All Arg/Lys at P2
102
103
104
105
106
Controllers
ViralLoad
![Page 52: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/52.jpg)
HIV Gag p24 KK10 epitope
HLA B27 molecule
I
W
K
I L
K
GL
R L
KM
HLA B27 molecule
I
W
K
I L
K
GL
![Page 53: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/53.jpg)
100%
80%
60%
40%
20%0%
n=21 86%
n=6 33%
p=0.02
PediatricAdult
2.73% CD8s
1.55% pbmc
IFN-
CD
8
B27-KK10 is recognized more frequently in adult than in pediatric HIV infection
![Page 54: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/54.jpg)
B27-ve mother B27+ve mothers
2000
1600
1200
800
400
0
043-C
0 0 0
002-C 048-C 049-C
IFN-SFC/million PBMC
1925
B27-KK10 is not recognized in children of B27-positive mothers
![Page 55: The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School](https://reader036.vdocuments.site/reader036/viewer/2022081506/56649cda5503460f949a47ae/html5/thumbnails/55.jpg)
2000
1600
1200
800
400
0
B27-ve mother B27+ve mothers043-C
0 0 0
002-C 048-C 049-C
B27-KK10 non-recognition associated with P2 anchor mutation
IFN-SFC/million PBMC
P2 anchormutationshared withmother
No P2 anchormutation