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expression: CD86 is expressed earlier than CD80 after B-cell activation and is
mostly detected on centrocytes, whereas CD80 is most strongly expressed on
centroblasts ( Vyth Dreese et al., 1995). CD80 and CD86 have been detected on
T cells from HIV-infected patients (Wolthers et al., 1996) and patients with
autoimmune disorders ( Wyss-Coray et al., 1993). Their high level of expression
on T cells, probably due to continuous immune activation, is generally asso-
ciated with low levels of CD28 expression ( Ha¨ar et al., 1995). Nevertheless,
CD86 expression seems to be restricted to the CD28
cells. Despite its low level
of expression on HIV-infected T cells, the stimulation of CD28 greatly increases
HIV-1 replication and T-cell growth (Asjo et al., 1993). Consistent with recent
data suggesting that CD80 and CD86 have nonoverlapping physiological
functions ( Freeman et al., 1995), we showed that HIV-1 replication induced by
T/B costimulation was mainly controlled by CD86-mediated interactions. In-
deed, CD86 mAb inhibited HIV-1 replication by 80% whereas CD80 mAb gave
only 30% inhibition. Similarly, B-cell-induced T-cell proliferation was inhibited
by 50% in the presence of CD86 mAb but by <10% with CD80 mAb. Additive
e¨ects were observed in the presence of CD86 mAb and CD80 mAb, with HIV-
1 replication inhibited by
b
90% and T-cell proliferation inhibited by 50±70%.
The e¨ects of these mAb on HIV-1 replication re¯ect their capacities to elicit
distinct pro®les of cytokines. CD86 mAb and CD80 mAb inhibited IL-2 pro-
duction by 77±98%. TNF-a production was inhibited by 84% and 43% in the
presence of CD86 mAb and CD80 mAb, respectively, whereas interferon
( IFN )-g production was inhibited by 54% by CD86 mAb but was una¨ected by
CD80 mAb. This suggests that, in the absence of IL-2, the residual TNF-a and
IFN-g present in CD80 mAb-treated cultures were su½cient to maintain a sig-
ni®cant level of HIV-1 replication and T-cell proliferation. This hypothesis
is supported by the fact that the addition of neutralizing anti-TNF-a mAb
increased CD80-induced inhibition whereas recombinant TNF-a partially re-
versed the CD86-induced inhibition of p24 production. No signi®cant dif-
ference in intracellular signaling has been demonstrated between CD80- and
CD86-mediated triggering of counterreceptors ( Rudd, 1996), but it is well
known that these molecules cause di¨erent functional outcomes in T cells
( Boussiotis et al., 1996; Kuchroo et al., 1995). Although both HIV-1 replication
and T-cell proliferation were increased by B-cell costimulation, the rate of viral
replication did not closely correlate with the level of T-cell proliferation. Even
in the presence of both CD80 mAb and CD86 mAb, which inhibited almost all
IL-2 and TNF-a production and two thirds of IFN-g production, T-cell pro-
liferation only decreased by 60%. Thus, intrinsic costimulatory signals delivered
by CD28/B7 interactions may independently control virus replication and T-
cell proliferation. Independent control of cell proliferation and viral replication
by cytokines has also been suggested by Smithgall et al. (1996). By increasing
T-cell proliferation, CD86-dependent interactions may not only enhance HIV-1
production in already infected T cells but may also favor de novo T-cell infec-
tion. These results suggest that CD86-mediated interactions may be essential
for B cell-driven active in situ replication of HIV-1 in GC T cells. The largest
