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redirected the site of virion budding and release from the plasma membrane to
intracellular Golgi-derived vacuoles (Biswas et al., 1992). Noteworthy, intra-
cellular accumulation of new progeny virions is a distinctive feature of macro-
phage infection observed in primary cells infected in vitro (Gartner et al., 1986;
Gendelman et al., 1988) as well as in vivo (Orenstein et al., 1997).
In addition to IFN-g, virtually all the major anti-in¯ammatory cytokines,
namely IL-4, IL-10, and TGF-b, have been associated with either enhance-
ment or suppression of viral replication ( Emilie et al., 1992; Kazazi et al., 1994;
Lazdins et al., 1991, 1992; Poli et al., 1992; Schuitemaker et al., 1992). In the
case of IL-10, HIV replication was inhibited in primary MDM stimulated at
concentrations fully suppressing the synthesis of TNF-a and IL-6, whereas ex-
ogenous addition of these pro-in¯ammatory cytokines (at concentrations com-
parable to those secreted from control MDM) overcame the inhibitory e¨ect of
IL-10 (Weissman et al., 1994). Furthermore, when MDM were treated with
suboptimal concentrations of IL-10, a moderate enhancement and not inhi-
bition of virus production was observed. IL-10 synergized with both TNF-a
and IL-6 in the induction of viral expression in chronically infected U1 cells
( Weissman et al., 1995). In addition, IL-10, unlike other anti-in¯ammatory
cytokines, did not diminish virus expression in U1 cells sequentially stimulated
with GM-CSF and LPS, a combination leading to the activation of an IL-1b/
IL-1ra dependent autocrine loop controlling HIV production (Goletti et al.,
1996).
It is likely that several opposite e¨ects on virus replication described for a
given cytokine are also consequent to modulatory e¨ects exerted on chemokine
entry co-receptors (mostly CCR5 and CXCR4). Indeed, both IL-4 (Schuite-
maker et al., 1992) and IL-10 have been shown to favor infection of freshly
isolated monocytes (usually more resistant to infection than MDM). In the case
of IL-10, this e¨ect was clearly associated to the enhanced expression of CCR5
and CCR5-dependent entry of HIV-1 (Sozzani et al., 1998). A divergent role
has been described for IL-4 on the two main entry co-receptors, in that it en-
hanced CXCR4 expression and decreased CCR5 levels in T cells (Galli et al.,
1998; Jourdan et al., 1998; Valentin et al., 1998). In addition, Th1 cytokines
such as IL-12 and IFN-g have also been reported to in¯uence CXCR4 (Shirazi
and Pitha, 1998) and CCR5 expression and/or infectability of MDM ( Har-
iharan et al., 1999; Wang et al., 1999) or U937 promonocytic cells (Zella et al.,
1998). Thus, all the major cytokines in¯uencing Th1 vs. Th2 immune response
show important modulatory e¨ects on HIV entry co-receptors on both macro-
phages and T cells (Sallusto et al., 1998). It should, however, be underscored
that di¨erent levels of cell surface expression may not necessarily translate into
substantial di¨erences in terms of susceptibility of the target cell to viral infec-
tion and spreading. In this regard, we have recently described a ``cytokine-like''
activity of CCR5-dependent HIV in T cells maintained in IL-2 enriched me-
dium but not mitogenically stimulated by anti-CD3 mAb, a condition that was
instead indispensable for the e½cient spreading of CXCR4-dependent HIV-1
( Vicenzi et al., 1999). On the other hand, extracellular Tat inhibited entry and
