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HIV – FIV - LCMV
• Immune system + viruses
• Tricks of pers. V:
T deletion / escape
nAb delay / escape
• Re-encountered / persistent antigen
maintains nAb (successful vaccines) and
act. T (infection immunity: no vaccine) for
protection
LCMV blood titer (log10 pfu)
LCMV-viremia control or nAb escape
S1
S2
S3
7
6
5
4
S5
S6
S7
S8
3
2
1
0
S7
6
nAb titer (log2 x 20)
50
100
150
S8
200
nAb against:
WE
V1
V2
V3
V4
V5
V6
5
4
3
2
1
0
0
100
200 0
100
200
days after infection with 2x106pfu LCMV-WE (i.v.)
Ciurea, Hunziker et al.
B
Ab
•
•
•
•
T
• Control-elim. intracell parasites
also in solid organs
• regulate longterm IgG
• cause imunopathology
(negative selection)
Prevent penetration IgA
systemic neutr.-opson.IgM/G
adoptive transferable IgG
IgM 1-2d, regulated by
Ag-dose and structure
(no negative selection)
reverse genetic glycoprotein exchange between LCMV and VSV
Pinschewer, de la Torre et al.
rLCMV/INDG
glycoprotein:IND-G
LCMV
glycoprotein: LCMV-GP
rVSV/LCMV-GP
glycoprotein: LCMV-GP
VSV-IND
glycoprotein:IND-G
Only VSVG expressing viruses induce a neutralizing antibody response
VSV-IND neutralization
rLCMV/INDG neutralization
12
10
8
6
4
2
<1
12
10
8
6
4
2
<1
3
8
14
20
time after infection (days)
3
8
14
20
time after infection (days)
LCMV-ARM neutralization
rVSV/LCMV-GP neutralization
12
10
8
6
4
2
<1
12
10
8
6
4
2
<1
3
8
14
20
time after infection (days)
3
8
14
20
time after infection (days)
total Ig
2x10 4 PFU rLCMV/INDG i.v.
2x10 4 PFU LCMV i.v.
2x10 4 PFU VSV-IND i.v.
2x10 4 PFU rVSV/LCMV-GP i.v.
2x10 7 PFU rVSV/LCMV-GP i.v.
IgG
LCMVHIS
WEN-3 mAb
Neutralising Ab: GP structure
early:
TH independent IgM, germline
high affinity / avidity
late:
immunosuppression ?
affinity maturation?
Hypergammaglobulinemia vs. neutralizing antibodies
15
control
anti CD8
6
CD8 -/-
5
control
anti CD8
4
CD8 -/-
10
5
0
0
10
20
30
40
50
time after infection (days)
Recher, Lang, Hunziker 2004
60
Neutralising antibodies
8
7
Neutralising titer
(log 2) X 10
20
Neutralising antibodies
Neutralising titer
(log 2) X 10
Serum Immunglobulins
(% of total serum proteins)
Hypergammaglobulinemia
3
2
6
5
4
2
1
1
<1
<1
0
10
20
30
40
time after infection (days)
50
60
WE anti CD4 (1 :100)
WE
3
0
10
20
30
40
time after infection (days)
50
60
Conclusion:
• Many nAb "specificities" control V, if "one" too
slow/low: V-escape!
• Hypergammaglobulinemia and polyclonal B cell
activation compete with nAb responses and seem
to depend upon amount of virus-specific CD4
T cells.
• Mechanisms of B cell competition? (Cytokine
receptor competition? Anatomic competition in
germinal centers? Competition for anti-apoptotic
cytokines?).
Memory vs. Protection
First infection kills host:
no memory needed
Host survives first infection:
memory not necessary
Why autoimmune disease in
humans mostly via antibodies?
Why
>>
!
Why all vaccines that function protect
via neutr. antibodies?
No protection by Memory B cells but
protection by immune serum in
_/_
IFN-aBR against VSV
Anti-VSV
neutr. AB
% Survivors
VSVIND immune
spleen cells T+B
<1:
40
0
LCMV immune
spleen cells
<1:
40
0
VSVIND Ab
< 1 : 2500
100
Maintenance of protection
1. Agent persists: TB, leprosy, HIV, HCV, LCMV
Herpes viruses
crippled: measles?
2. Repetitive inf.: polio, bact. toxins
3. Antibody-antigen complex depots in lymph
nodes and spleens
persistent virus
from mother
Poliomyelitis – age distribution in
Massachusetts 1912 – 1952
Years
1912-1916
1930-1934
1948-1952
Percent
Percent
0 – 4 years 5 – 9 years
70
28
18
18
38
27
Percent
10+ years
12
34
55
Modified from: Nathanson,N. Am J Epidemiol 1979; 110:672-692.
Memory / Pregnant Female
• Academic: earlier + higher (AG –)
• Immune against cytopathic infections
otherwise abortions / malformations
• MHC-incompatibility – offspring / mother
• Maternal antibodies attenuate acute infections
physiological vaccinations (incl. malaria, eggs)
• Non-cytophatic infections transferred via placenta / at
birth / after birth (LCMV, HCV, Herpes)
• Resistance via T cells: HIV, HTV, TB Lepr. slow
• "Emerging" infections
Conclusions:
Persistent infections
numbers / variability
• T cell control – immunopathology – "tolerance"
• nAb essential (affinity maturation?) or escape
• antigen maintains nAb titers and act. T cells
(but immunopathology!)
• All successful vaccines: nAb
not successful: should (also) maintain
act.T (not achieved yet)
H. Hengartner
E.
A.
L.
M.
U.
Battegay
Ciurea
Hunziker
Recher
Steinhoff
B. Odermatt
Th.Leist
K. Lang
D. Pinschewer
J. de la Torre
IMMUNITY
• “innate resistance“ > 95 %
•
•
•
•
Ab in eggs
protective memory via Ab (vaccines)
TB: no vaccine
autoimmunity > 30 y, female > male
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