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hyperplastic HIV lymph nodes ( Legendre et al., 1998). Persistent HIV infec-
tion is accompanied by progressive and irreversible destruction of lymphoid
organs involving not only CD4 T cells, but also B cells and FDC ( Baroni and
Uccini, 1990; Heath et al., 1995; Spiegel et al., 1992).
These data show that HIV-1 induces strong B-cell activation and the dis-
organization of lymphoid tissue. Besides impairing cell-cell interactions and
cytokine production, we thought that these functional and phenotypic changes
result from direct interactions between virions and B cells. We have therefore
studied over the last few years the mechanisms by which HIV-1 alters the vari-
ous steps of B-cell di¨erentiation and may actively participate in lymphoid
tissue disorganization and disease progression.
NORMAL B-CELL DIFFERENTIATION AND TRAFFICKING
In the absence of antigenic stimulation, mature B and T lymphocytes con-
tinuously pass from the blood into the lymphoid tissue. Contact with the anti-
gen (Ag) that occurs in the epithelia of skin or mucosa induces the recirculation
of immature dendritic cells ( DC) into the draining lymphoid organ (Cyster,
1999). The binding and uptake of Ag result in the maturation of DC and their
relocation to the junction between the extrafollicular zone of the lymphoid
tissue, rich in T lymphocytes, and the external area of the follicles, rich in B
lymphocytes (Cyster, 1999). At this site, Ag presented by mature DC inde-
pendently activates B and T lymphocytes with the same antigenic speci®city,
preventing their further recirculation ( Liu, 1997; McHeyzer-Williams et al.,
1993; Melchers et al., 1999). An e½cient T-dependent humoral response is only
achieved if these Ag-activated B and T lymphocytes rapidly establish direct cell-
cell interactions, allowing the B cells to survive, to di¨erentiate into plasmo-
cytes producing immunoglobulin (Ig)M with low a½nity for the Ag, and to
generate GC founder cells (Goodnow and Cyster, 1997; Liu, 1997; Melchers
et al., 1999). Within GC, B lymphocytes are subjected to several cycles of a
sequence of events: a clonal expansion phase during which VDJ hypermuta-
tions generate antibody variants (dark zone of GC, centroblasts) followed by a
second phase involving the arrest of cell proliferation, isotype switching, and
the selection of centrocytes expressing B-cell antigen receptor (BCR) with high
a½nity for the Ag (light zone of GC) ( Berek et al., 1991; Kelsoe, 1996; Liu
et al., 1992). Hypermutation and subsequent selection of variants that bind
Ag strongly result in a progressive increase in Ab a½nity, a process known as
a½nity maturation ( French et al., 1989; Gri½ths et al., 1984). Both negative
and positive selection processes control a½nity maturation. Negative selection,
leading to a massive apoptosis, is favored by the down-regulation of Bcl-2 and
the strong expression of Fas (CD95) in GC B cells (Martinez-Valdez et al.,
1996; Smith et al., 1995). Several pathways may lead to GC B-cell apoptosis:
BCR triggering in the absence of T-cell signals, ligation of CD95 by CD95L-
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