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onstrated that the IL-2 receptor can generate at least three distinct signaling
pathways leading to the activation of c-fos/c-jun (AP1), c-myc, and Bcl-2, all
essential for IL-2-mediated proliferative signaling. Furthermore, these pathways
cooperate with each other to ensure a full-scale cellular activation (Minami et
al., 1993).
Concerning HIV infection, it is frequently assumed that IL-2 will stimulate
HIV expression, based on its capacity to induce activation and proliferation of
T and B lymphocytes. However, IL-2 induces strong cellular proliferation, but,
unlike PMA, fails to activate HIV-1 LTR-driven transcription in primary T-cell
clones activated in an antigen-restricted manner ( Hazan et al., 1990). In addi-
tion, IL-2-stimulated PBMC support e½cient virus replication that is consequent
to the release of pro-in¯ammatory cytokines such as TNF-a, IL-1b, and IFN-g
acting in an autocrine/paracrine fashion ( Kinter et al., 1995b; Vyakarnam et
al., 1990). IL-2 was later shown to activate HIV replication (presumably with
the same general mechanism) in PBMC and mononuclear cells extracted from
lymph nodes of infected individuals and cultivated ex vivo, but unlike IL-12,
only when CD8
T cells were removed ( Kinter et al., 1995a, 1996). Thus, IL-2
up-regulated the production of soluble suppressor factors from CD8
T cells
(simultaneously described as dependent from b chemokines or IL-16 by inde-
pendent groups [Baier et al., 1995; Cocchi et al., 1995]) and natural killer ( NK)
cells (Oliva et al., 1998) that tilted the balance toward virus suppression. This
e¨ect of IL-2 is currently discussed as one of the potential correlates of the in
vivo e¨ect of the cytokine once administered to HIV-infected individuals.
Experimental administration of IL-2 was begun in the 1980s after the ob-
servation of a relative defect of IL-2 synthesis in infected individuals (Murray et
al., 1984). Two main protocols are currently investigated: a low-dose (< 1
MIU/day) delivered continuously per subcutaneous (sc) route (Fehniger et al.,
2000; Khatri et al., 1998) vs. administration of intermittent cycles of higher
doses of IL-2 (from 3 to 15 MIU/day) given sc for 5 days every 4±8 weeks
(Kovacs et al., 1995, 1996). This second approach is currently being evaluated
for clinical e½cacy in two large-scale international trials (SILCAAT and ES-
PRIT ). The former ``low-dose'' approach is also currently being investigated,
and has resulted in substantially increased levels of NK cell activity, without
substantial alteration of the representation of PBMC subsets in the periphery.
In contrast, the intermittent ``high-dose'' approach leads reproducibly to a very
signi®cant increase of circulating CD4
T-cell numbers reaching normal or
near normal levels. Although ``high-dose'' IL-2 administration has resulted in
spikes of virus replication in vivo, these were transient in nature and did not
alter the set-point of plasma HIV RNA (viremia) (Kovacs et al., 1995), an im-
portant prognosticator of disease progression (Mellors et al., 1996). In this
regard, we have recently described a down-regulation of Ying/Yang-1 (YY1)
and Leader binding protein-1 ( LBP-1)/late SV40 factor ( LSF ), which bind to
common sequences in the virus LTR and exert a silencing e¨ect on viral tran-
scription in individuals receiving ``high-dose'' IL-2 therapy (Bovolenta et al.,
1999b). As discussed above, IL-2 can also activate HIV-suppressive mecha-
