HIV – FIV - LCMV

• Immune system + viruses• Tricks of pers. V:

T deletion / escapenAb delay / escape

• Re-encountered / persistent antigen maintains nAb (successful vaccines) and act. T (infection immunity: no vaccine) for protection

LC

MV

blo

od t

iter

(lo

g10

pfu

)

0 50 100 150 200

1

2

3

4

5

67

S7S8

S1S2

S3

S5S6

Tim e dependence of LCM V-virem ia: long-term contro l or escape

LC

MV

blo

od

tite

r (l

og1

0 p

fu)

0 50 100 150 200

1

2

3

4

5

67

S7S8

S1S2

S3

S5S6

LCMV-viremia control or nAb escape

Ciurea, Hunziker et al.

• Prevent penetration IgA• systemic neutr.-opson.IgM/G• adoptive transferable IgG• IgM 1-2d, regulated by

Ag-dose and structure(no negative selection)

• Control-elim. intracell parasites also in solid organs

• regulate longterm IgG• cause imunopathology

(negative selection)

T

BAb

glycoprotein: LCMV-GP glycoprotein:IND-G

rLCMV/INDG rVSV/LCMV-GP

reverse genetic glycoprotein exchange between LCMV and VSVPinschewer, de la Torre et al.

LCMV VSV-IND

glycoprotein: LCMV-GPglycoprotein:IND-G

Only VSVG expressing viruses induce a neutralizing antibody response

3 8 14 20

642

108

12

<1

time after infection (days)

642

108

12

<13 8 14 20

time after infection (days)

VSV-IND neutralization rLCMV/INDG neutralization

3 8 14 20time after infection (days)

642

108

12

<1

rVSV/LCMV-GP neutralization

3 8 14 20time after infection (days)

642

108

12

<1

LCMV-ARM neutralization

2x104 PFU rLCMV/INDG i.v.

2x104 PFU VSV-IND i.v.

2x104 PFU LCMV i.v.

2x104 PFU rVSV/LCMV-GP i.v.

2x107 PFU rVSV/LCMV-GP i.v.

total Ig IgG

LCMV HIS

WEN-3 mAb

Neutralising Ab: GP structure

early: TH independent IgM, germlinehigh affinity / avidity

late: immunosuppression ?affinity maturation?

0 10 20 30 40 50 600

5

10

15

20controlanti CD8

CD8 -/-

time after infection (days)

Seru

m Im

mun

glob

ulin

s(%

of t

otal

ser

um p

rote

ins)

Hypergammaglobulinemia Neutralising antibodies

0 10 20 30 40 50 60

<1

anti CD8control

1

2

3

4

5

6

CD8 -/-

time after infection (days)

Neu

tralis

ing

titer

(log

2) X

10

0 10 20 30 40 50 60

<1

WEWE anti CD4 (1 :100)

1

2

3

4

5

6

7

8

time after infection (days)

Neu

tralis

ing

titer

(log

2) X

10

Neutralising antibodies

Hypergammaglobulinemia vs. neutralizing antibodies

Recher, Lang, Hunziker 2004

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 CD4T cells.

• Mechanisms of B cell competition? (Cytokine receptor competition? Anatomic competition in germinal centers? Competition for anti-apoptotic cytokines?).

Why autoimmune disease inhumans mostly via antibodies?

Why >> !Why all vaccines that function protect via neutr. antibodies?

First infection kills host:no memory needed

Host survives first infection:memory not necessary

Memory vs. Protection

No protection by Memory B cells but protection by immune serum in

IFN-aBR_/_ against VSV

VSVIND immunespleen cells T+B

LCMV immunespleen cells

VSVIND Ab

Anti-VSVneutr. AB

< 1 : 40

< 1 : 40

< 1 : 2500

% Survivors

0

0

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 virusfrom mother

Poliomyelitis – age distribution in Massachusetts 1912 – 1952

Years Percent0 – 4 years

Percent5 – 9 years

Percent10+ years

1912-1916 70 18 121930-1934 28 38 341948-1952 18 27 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: nAbnot successful: should (also) maintainact.T (not achieved yet)

H. Hengartner

E. Battegay

F. Ciurea

L. Hunziker

M. Recher

U. Steinhoff

B. Odermatt

Th. Leist

K. Lang

L. Pinschewer

J. de la Torre

IMMUNITY

• “innate resistance“ > 95 %

• Ab in eggs

• protective memory via Ab (vaccines)

• TB: no vaccine

• autoimmunity > 30 y, female > male5 : 1