Download Reduced CXCR5 expression on B cells during HIV-1

Routine vaccination and maintenance of serological memory
in HIV infected children
Moderators: Berhanu Gudeta, Ethiopia
Francesca Chiodi, Sweden
Cell Damage during HIV infection
Francesca Chiodi, Sweden
Vaccination of immuno-compromised children and mechanisms
of long-term serological memory
Anna Nilsson, Sweden
Novel therapy approaches to restore antibody responses
during HIV infection
Kehmia Titanji, Cameroon and USA
Towards therapeutical HIV vaccination and ameliorated
vaccination schedules in HIV infected children
Britta Wahren, Sweden
Cell damage during HIV-1 infection
Francesca Chiodi
Several B cell abnormalities were reported to occur
during HIV-1 infection.
• loss of antibodies to vaccination antigens and antigens
previously met in life
• high level of circulating IgG (hypergammaglobulinemia)
of unknown specificity
• hyperactivated status of B cells (and other cells of the
immune system) as detected by surface markers
• declined number of memory B cells (resting)
• increased number of circulating transitional B cells,
activated and tissue like memory B cells
Antibodies are important components of effective vaccines
Rino Rappuoli, Novartis
Vaccines should induce long-term serological memory
Mechanisms suggested for maintaining long-term antibody responses
Polyclonal stimuli
derived from
2
1
Stimulation of
memory B cell
Persisting antigens
Non-cognate T cell help
or microbes (CpG or LPS)
3
Plasma cell
The maintenance of serum antibodies
requires the continuous proliferation
and differentiation of memory cells
into antibody-secreting plasma cells
Long-lived plasma cells
HIV-1 infection leads to deletion of memory B cells accompanied
by loss of serological memory; these dysfunctions start already
during primary HIV-1 infection
100
P<0.001
60
40
Anti-measles IgG
CD27+ B cells (%)
80
20
20
18
16
14
12
10
8
6
4
2
0
P<0.01
0
Controls
Loss of memory B cells
CHI
LTNP
Loss of antibodies
3500
Anti-pneumococcus IgG
Controls PHI
CHI
LTNP
(n=34) (n=41) (n=80) (n=14)
PHI
De Milito A et a., Blood 2004; Titanji K et al., Blood 2006
3000
P<0.001
n.s.
P<0.001
2500
2000
1500
1000
500
0
Controls
PHI
p<0.02
CHI
LTNP
Studies to understand the mechanisms leading to
depletion of memory B cells may result in:
a) Improved vaccination for HIV-1 infected children
and adults
b) Novel immunomodulatory therapy to improve
B cell immunology
Some examples in that direction…
Two phase-model for depletion of memory B cells from circulation
Altered migration
Apoptosis
Chiodi, Journal of Clinical Investigation 2010
ALTERED EXPRESSION OF THE RECEPTOR-LIGAND PAIR CXCR5/CXCL13 IN
B-CELLS DURING CHRONIC HIV-1 INFECTION
CXCR5 directs B cell migration into lymphoid organs.
CXCL13, the ligand, is secreted by stromal cells, FDCs and T(FH) cells in B cell follicles.
Alberto Cagigi and Anna Nilsson Blood, 2008
Reduced CXCR5 expression on B cells during HIV-1
infection, in relation to CD4+ T cells
Increased levels of CXCL13 (both mRNA and ex-vivo secretion)
were detected in purified B cells from HIV-1 infected patients
Altered expression of the chemokine receptor-ligand pair,
CXCR5/CXCL13 may participate in the impairment of B cell homing
and establishment of B-cell dysfunctions during HIV-1 infection.
Increased cell-death of B cells may take place during HIV-1 infection
T and B cells are primed for apoptosis during HIV-1 infection and
Fas is an important molecule in this context
HIV-1 infection leads to Fas upregulation on B cells
Changes in Fas expression in 31 patients with primary HIV infection treated with ART
Naive B cells
Memory B cells
Fas expression (%)
120
100
p=0.003
p<0.001
80
60
40
20
p=0.42
0
Controls
p<0.01
0
6
Duration of therapy
(months)
PHI
Controls
0
6
Duration of therapy
(months)
PHI
ART leads to a decline, but not normalization, of Fas expression on B cells
Fas is high during chronic HIV infection
K Titanji et al., AIDS 2005
IL-7 promotes Fas expression on B cells via IFN-γ
released from IL-7 treated T cells
Sammicheli S et al., PLoS ONE 2011
PD-1 signaling is highly involved in
B cell survival signals
Fp7 EU project
Thanks to:
Next Generation HIV-1 Immunogens inducing
broadly reactive Neutralising antibodies
European Vaccines and Microbicides Enterprise
Fp6 Network of excellence 2007-2011
Swedish MRC
Swedish International
Development Cooperation
Agency
Karolinska
Institutet