Biology Reference
In-Depth Information
trocyte populations in HIV
LNs. Despite the strong GC depolarization typical
of HIV
hyperplasia, the expression of most B-cell markers is similar in HIV
and HIV
ÿ
lymph nodes. The most striking result is the loss of CD80 from the
GC, with CD86 levels unchanged. Experiments are underway in experimentally
infected macaques to clarify whether (i) GC depolarization and the loss of
CD80 expression in GC occur progressively or are already detectable after
primo-infection; (ii) the development of these B cell abnormalities is dependent
on T-dependent Ag stimulation; and (iii) antiretroviral tritherapy restores ex-
pression of CD80 in lymphoid tissue. Preliminary results in simian-human im-
munode®ciency (SHIV )-infected macaques suggest that the development of GC
hyperplasia requires repetitive Ag challenge in addition to viral infection.
HIV-1 TAT PROTEIN: A POTENT MODULATOR OF B-CELL
FUNCTIONS
Previous reports have shown that soluble gp120, Vpr, Nef, and Tat are present
as biologically active extracellular proteins released by infected cells in HIV
patients ( Westendorp et al., 1995). Extracellular Nef and gp120/160 increase
terminal di¨erentiation of B cells into Ig-producing cells by increasing T/B
interactions and monocyte-derived IL-6 production (Chirmule et al., 1993,
1994). Extracellular Tat, readily taken up by uninfected cells and targeted to
the nucleus (Frankel and Pabo, 1988), stimulates the growth of Kaposi's sar-
coma cells, potentiates the anergy and apoptosis of uninfected T cells, and
promotes chemotaxis and invasive behavior by monocytes (Albini et al., 1998;
Lafrenie et al., 1996; Rubartelli et al., 1998). In B-cell lines, Tat also modulates
the production of cytokines and their receptors ( Puri and Aggarwal, 1992;
Sharma et al., 1995). It also increases CD95 expression on peripheral B cells
during short-term cocultures with T cells and monocytes ( Huang et al., 1997).
Recent data also showed that viral protein R (Vpr) acts as a proapoptotic agent
in monocytes and T cells (Jacotot et al., 2000). Thus, these accessory proteins,
locally produced in the lymphoid organs of HIV
patients, might directly act
on primary B cells and contribute to the B-cell abnormalities observed in vivo.
We have recently established that extracellular Tat, unlike recombinant Nef,
exerts a direct e¨ect on all primary B-cell subsets, but di¨erentially modulates
the anti-IgM Ab- and CD40 mAb-induced proliferation of naive, memory, and
GC B-cell subsets isolated from the lymphoid organs of HIV
ÿ
donors (Fig. 5.6)
(Lefevre et al., 1999). Indeed, Tat strongly inhibits the proliferation of BCR-
triggered naive and memory B cells but has no e¨ect on their CD40 mAb and
cytokine (IL-4 or IL-2 plus IL-10) mediated cell proliferation. In contrast, Tat
doubles the GC B-cell proliferation induced by CD40 mAb and IL-4. These
functional e¨ects of Tat are (i) dose-dependent with a maximal e¨ect obtained
between 0.5 and 1 mg/ml (0.05±0.1 mM) for 10
6
cells/ml (these concentrations
are higher than the serum concentration, 0.01±0.5 nM, reported for HIV-1
patients but similar to those used in vitro with T cells, 0.5 nM to 2 mM; (ii)
