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Saharan Africa, has three binding sites for NF-kB and its replication is more
potently upregulated by TNF-a in vitro in comparison to that of other HIV
clades with one or two binding sites (De Baar et al., 2000; Jeeninga et al., 2000;
Montano et al., 2000).
The presence of functional binding sites for NF-kB in the virus LTR has
been usually associated with the total loss of responsiveness to TNF-a, whereas
other stimuli, such as phorbol esters, could maintain their e¨ects, at least in
part (Antoni et al., 1994). However, more recently, AP1-mediated transcription
consequent to the activation of ERK-1, ERK-2 and, MAP kinases has also
been demonstrated to activate virus expression in chronically infected U1 cells
stimulated with TNF-a ( Yang et al., 1999).
Like TNF-a, IL-1 a/b has also demonstrated the capacity of inducing viral
replication. However, IL-1 failed to activate NF-kB (Poli et al., 1994b), but
likely operates via p38 MAPK in chronically infected U1 cells (Shapiro et al.,
1998a). Upregulation of HIV through the activation of p38 MAPK and NF-kB
was also observed after stimulation with IL-18, although these studies did not
rule out a possible role of endogenous TNF-a and IL-6, cytokines that are also
induced by this recently identi®ed cytokine (Shapiro et al., 1998b).
Unlike TNF-a or IL-1b, a post-transcriptional mechanism of up-regulated
HIV expression (likely involving modulation of the Rev/RRE axis of HIV
RNA nucleus to cytoplasm export) was early identi®ed in U1 cells stimulated
with IL-6 ( Poli et al., 1990).
In addition to tumor cell lines, it has been formally proven that stimulation
by individual cytokines such as IL-2, IL-7, IL-12, or a cytokine combination
such as TNF-a plus IL-2 and IL-6 could also induce HIV replication in primary
cells infected in vitro and from PBMC and latently infected resting memory
CD4 T lymphocytes infected in vivo with HIV (Chun et al., 1998; Kinter et
al., 1995a, b). In this regard, B lymphocytes from infected individuals, known
to be polyclonally activated in vivo, are important chaperones of viral particles
(Moir et al., 2000) and a source of HIV-inductive cytokines such as TNF-a, IL-
6, and, potentially, IL-7 ( Benjamin et al., 1994). Indeed, B lymphocytes have
been shown to induce viral replication from both chronically infected cell lines
and autologous CD4 T cells of HIV-infected individuals (Rieckmann et al.,
1991a, b).
HIV INHIBITORY CYTOKINES
Among the few clear-cut HIV suppressive cytokines, type I IFNs (IFN-a/b and
IFN-g) play an important role. IFN-a, in particular, has shown potent anti-
HIV activities in vitro by inhibiting multiple steps of the virus life cycle, in-
cluding reverse transcription and transcription of integrated provirus in acutely
infected primary cells ( Poli et al., 1994a). In addition, type I IFNs inhibited the
release of new progeny virions from the cell surface in chronically infected cells
(``post-budding'' e¨ect) ( Poli et al., 1989). Despite a demonstrated antiviral
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