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 Persisting antigens Plasma cell Long-lived plasma cells The maintenance of serum antibodies requires the continuous proliferation and differentiation of memory cells into antibody-secreting plasma cells Stimulation of memory B cell Non-cognate T cell help or microbes (CpG or LPS) Polyclonal stimuli derived from 1 2 3

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 De Milito A et a., Blood 2004; Titanji K et al., Blood 2006 Controls PHI CHI LTNP Anti-measles IgG P<0.01 Controls PHI CHI LTNP Anti-pneumococcus IgG P<0.001 n.s. p<0.02 Controls PHI CHI LTNP (n=34) (n=41) (n=80) (n=14) CD27+ B cells (%) P<0.001 Loss of memory B cells Loss of antibodies

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…

Chiodi, Journal of Clinical Investigation 2010 Two phase-model for depletion of memory B cells from circulation Altered migration Apoptosis

ALTERED EXPRESSION OF THE RECEPTOR-LIGAND PAIR CXCR5/CXCL13 IN B-CELLS DURING CHRONIC HIV-1 INFECTION Alberto Cagigi and Anna Nilsson Blood, 2008 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.

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.

T and B cells are primed for apoptosis during HIV-1 infection and Fas is an important molecule in this context Increased cell-death of B cells may take place during HIV-1 infection

ART leads to a decline, but not normalization, of Fas expression on B cells Fas is high during chronic HIV infection

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

European Vaccines and Microbicides Enterprise Fp6 Network of excellence Thanks to: Swedish MRC Swedish International Development Cooperation Agency Karolinska Institutet Fp7 EU project Next Generation HIV-1 Immunogens inducing broadly reactive Neutralising antibodies