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activity in vivo as a monotherapy agent, and the additional bene®cial e¨ects
observed in AIDS patients with Kaposi' sarcoma ( Lane et al., 1988), IFN-a/b
are not usually considered in highly aggressive antiretroviral therapy ( HAART )
trials, mainly because of their substantial toxicity. However, the availability of
PEGylated forms of IFN-a, characterized by a prolonged half-life and easier
compliance, may lead to a rediscovery of this classical antiviral molecule.
Similar to IL-4, but produced by macrophages, IL-13 was shown to be a
potent inhibitor of HIV replication in monocyte-derived macrophages (MDM)
but not in activated T lymphocytes (Montaner et al., 1993, 1997). Furthermore,
IL-13, like IL-4, inhibited bacterial lipopolysaccharide-induced HIV expression
in GM-CSF-stimulated chronically infected U1 cells. A crucial mechanism
appeared to be the tilting of an endogenous IL-1b/IL-1 receptor antagonist
(IL-1ra) balance in favor of the latter (Goletti et al., 1996). In this regard, IL-
1ra remains the only natural example of a cytokine receptor antagonist, syn-
thesized in multiple isoforms and expressed both intracellularly and as secreted
molecule ( Dinarello, 1998), capable of suppressing HIV replication or expres-
sion (Kinter et al., 1995b; Muzio et al., 1995; Poli et al., 1994b). It should be
underscored that the unique mechanism of IL-1ra is the prevention of IL-1-
mediated signaling via interaction with the type I IL-1 receptors, and, therefore,
its suppressive e¨ect on virus multiplication is a formal proof of the opposite,
enhancing role of IL-1.
As mentioned earlier, IL-16, a physiological ligand of CD4, was early de-
scribed as being the potential correlate of the nonlytic CD8 antiviral activity
discovered in 1986 (Walker et al., 1986). Subsequent studies con®rmed that its
inhibitory e¨ect on viral transcription and expression (Mackewicz et al., 2000),
resembling independent reports describing similar e¨ects induced by some anti-
CD4 monoclonal antibodies (mAb) (Briant et al., 1999; Guillerm et al., 1998;
Monnet et al., 1999).
CYTOKINES WITH MULTIPLE EFFECTS ON HIV REPLICATION
Most cytokines exert opposite e¨ects on HIV replication in di¨erent experi-
mental conditions. IFN-g, for example, has been reported to inhibit HIV repli-
cation at both the entry and post-entry steps ( Poli et al., 1994a; Shirazi and
Pitha, 1998). Its antiretroviral e¨ect is the result of the activation of the JAK/
STAT pathway, following protein tyrosine kinase Pyk2 activation (Takaoka et
al., 1999). In addition, we have also described an antiviral e¨ect likely inde-
pendent from cell surface expression of the IFN-g receptor 2 chain and involv-
ing IFN-stimulated gene factor 3g ( ISGF3g), a transducer molecule typically
activated by IFN-a/b in subclones of the U937 cell line ( Bovolenta et al.,
1999c). In contrast to these inhibitory e¨ects, IFN-g activated HIV expression
in chronically infected U1 cells ( Biswas et al., 1992). Of interest, when U1 cells
were activated and di¨erentiated by phorbol esters, IFN-g appeared to exert a
suppressive activity. However, ultrastructural analysis revealed that it actually
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