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(Krzysiek et al., 1999). It is also unknown whether Tat modulates the re-
sponsiveness of B cells to SDF-1a, BCA-1, ELC, SLC, fractalkine, or TECK
(thymus-expressed chemokine), or the expression of their respective receptors,
thereby contributing to the abnormal relocation of B cells observed in HIV
patients.
Tat, by increasing GC B-cell proliferation, may play an important role in
HIV-associated centrofollicular hyperplasia. This hypothesis is supported by
the data of Kundu et al. showing that tat transgenic mice develop centro-
follicular hyperplasia and B lymphomas ( Kundu et al., 1999). Tat may also be
involved in the loss of the mantle zone in follicles and the progressive decrease
in the B-cell repertoire, by inhibiting cell cycle progression, Ag-speci®c T/B
interactions, and cytokine production in naive B and memory cells. Our data
raise numerous questions concerning the use of Tat as a therapeutic or vacci-
nation agent in HIV
patients. Several groups have reported that vaccination
with Tat proteins that have mutations in the cysteine-rich region, and are thus
incapable of transactivation, induces the production of speci®c Ab and limits
the progression of the disease (Cafaro et al., 1999; Caselli et al., 1999; Gallo,
1999; Gringeri et al., 1998, 1999). However, a recent article reported that simi-
lar mutated, but not wild-type, Tat proteins down-regulate the expression of
HLA Class I in T cells in vivo ( Tosi et al., 2000). We have also found that these
mutated Tat proteins are as e½cient as wild-type Tat at impairing the B-cell
response ( Lefevre et al., 1999). Based on these data, we think that repetitive Ag
challenges with T-dependent Ag should be included in all future therapeutic
trials using Tat and that the B-cell compartment in the lymphoid organs of
these monkeys should be carefully studied. From now on, it would be most
useful to design Tat proteins not only devoid of transactivating activity but also
unable to enter B cells (RGD or basic regions) or to be targeted to the nucleus
(nuclear localization signal region). Knowledge of the mechanisms by which
Tat exerts its e¨ects in B cells would provide new targets for therapeutic trials.
An alternative possibility for vaccination is the use of cyclic peptides derived
from Tat, as suggested by Friedler et al. (Friedler et al., 2000).
HIV-1 AND B-CELL LYMPHOMAGENESIS
In the absence of antiretroviral therapy, HIV
patients frequently develop high-
grade non-Hodgkin's lymphoma, known as AIDS-associated lymphoma. Most
of these lymphomas are of B-cell origin and there is frequent involvement of
extranodal sites, 25% in the central nervous system (CNS) and 75% in the
periphery (Ng and McGrath, 1998), giving rise to two histological groups:
large-cell and immunoblastic lymphoma and Burkitt's lymphoma. Studies of
Epstein-Barr virus ( EBV ) expression and of Ig and c-myc rearrangements have
shown that large-cell lymphomas are predominantly polyclonal and usually
lack EBV and c-myc rerrangements and Burkitt's lymphomas are monoclonal
with a high frequency of rearranged c-myc genes, whereas CNS lymphomas
