Biology Reference
In-Depth Information
B CELLS IN HIV
B
PATIENTS
Phenotypic and functional abnormalities of B cells are detectable soon after
HIV infection: most peripheral blood B cells of HIV
patients are large, cycling
cells with high levels of CD38, CD70, and human leukocyte antigen ( HLA)-
DR antigens but no CXCR5 (Amadori and Chieco-Bianchi, 1990; Amadori
et al., 1989; Forster et al., 1997; Lane et al., 1983; Martinez-Maza et al., 1987;
Wolthers et al., 1996). This has led to the suggestion that these cells are blast B
cells that have escaped from the GC as a result of disruption of the FDC net-
work or failure of the apoptosis process ( Forster et al., 1997). Peripheral B cells
spontaneously produce large amounts of commutated Ig of various isotypes,
consistent with a post-GC origin. Soon after primo-infection and at the begin-
ning of the asymptomatic phase, 20±50% of these Ab are directed against the
virus itself, but this HIV-speci®c part of the humoral response then progres-
sively decreases in favor of the production of HIV-unrelated Ab and auto-
antibodies ( Lane et al., 1983; Samuelsson et al., 1997). This suggests that
the process of a½nity maturation or the survival of the speci®c memory pool
is impaired during disease progression (Amadori and Chieco-Bianchi, 1990;
Bessudo et al., 1996). The physiological role of HIV-speci®c Ab is unclear, but
several authors have suggested that high concentrations of anti-gp120 and anti-
Tat antibodies slow down progression of the disease (Morris et al., 1998; Re et
al., 1995; Reiss et al., 1990). Recent data from vaccination trials using synthetic
Tat or recombinant gp160 proteins in experimentally infected monkeys or in
HIV
patients support this idea (Cafaro et al., 1999; Caselli et al., 1999; Gallo,
1999; Gringeri et al., 1998, 1999; Polacino et al., 1999). Although, they are
activated in vivo, B cells from HIV-1 patients are paradoxically poor Ig pro-
ducers after in vitro challenge by recall Ag and do not signi®cantly proliferate
in response to strong B-cell mitogens or anti-IgM Ab, which trigger the BCR
(Amadori and Chieco-Bianchi, 1990). In vitro, spontaneous Ig production de-
creases rapidly unless stimulated by the addition of IL-6. Given the essential
role of IL-6 in plasmablast survival and in terminal B-cell di¨erentiation and
the high serum levels of IL-6 in HIV
patients, it was suggested that monocyte-
derived IL-6 keeps the level of Ig production high in vivo (Amadori and
Chieco-Bianchi, 1990). The addition of recombinant Nef and gp120 from
HIV-1 to cultures of peripheral blood mononuclear cells (PBMC) was shown
to increase Ig production by stimulating monocyte-derived IL-6 production
(Chirmule et al., 1993, 1994). Within the lymphoid organs of HIV
patients,
FDC are probably the main source of IL-6. gp120 and Tat also modulate the
responsiveness of CD4
monocytes and T cells to various chemoattractants and
the expression of chemokine receptors ( Lafrenie et al., 1996; Secchiero et al.,
1999; Wang et al., 1998), suggesting that they may a¨ect recirculation in vivo.
gp120 protein also acts as a superantigen on VH3
B cells, biasing the B-cell
repertoire ( Berberian et al., 1991, 1993; Karray and Zouali, 1997; Karray et al.,
1998). Complex interactions occur between di¨erent regions of gp120 and VH3
and are probably independent of CD4/gp120 interactions (Neshat et al., 2000),
