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replication of syncytium-inducing (SI ) strains but not CCR5-dependent HIV
via binding to CXCR4 (Ghezzi et al., 2000). These two last observations pro-
vide potential mechanisms through which macrophage-tropic CCR5-dependent
viruses dominate SI viruses after transmission and in early HIV disease.
HIV INFECTION PERTURBS CYTOKINE EXPRESSION IN VITRO AND
IN VIVO
If several cytokines modulate HIV replication, viral infection or expression of
viral proteins can profoundly a¨ect cytokine expression. It was early noted that
the levels of pro-in¯ammatory cytokines are increased in HIV-infected in-
dividuals ( Fahey et al., 1998; Scott-Algara et al., 1991). In particular, the levels
of TNF-a and soluble TNF receptor II are better correlates of disease evolu-
tion than CD4
T cell counts and viremia, respectively ( Fahey et al., 1998). In
addition, increased levels of anti-in¯ammatory cytokines, such as IL-10 (Gallo
et al., 1994; Muller et al., 1998), and TGF-b ( Wahl et al., 1991), have been also
observed in vivo and reproduced during in vitro infection (Cota et al., 2000a;
McManus et al., 1998). Several viral proteins, such as Env, Tat (Ambrosino
et al., 1997; Buonaguro et al., 1994; Ito et al., 1998; Nath et al., 1999), Nef
(Collette et al., 1996, 1997; Swingler et al., 1999), or Vpr (Ayyavoo et al., 1997;
Poon et al., 1998) have demonstrated multiple e¨ects on cytokine expression. In
this context, a major shift from Th1- to Th2-dominant cytokine pro®les has
been early postulated to play a major role in the pathogenesis of infection, be-
cause several exposed but uninfected individuals could elaborate IL-2 secretion
or even CTL once their PBMC were challenged ex vivo with HIV peptides
(Clerici and Shearer, 1994). However, there has not been a clear-cut body of
evidence in favor of this general hypothesis, although Th2-polarized cells are
more prone to HIV replication (Maggi et al., 1994). In support of this hypoth-
esis, we have recently observed that primary HIV strains dualtropic for usage
of entry coreceptors e½ciently replicate in Th2 and Th0, but not Th1 cells
(E. Vicenzi et al., unpublished observations).
Clear evidence of the activation of the cytokine network as a consequence of
HIV infection has been recently provided by the demonstration of a constitutive
activation of STAT proteins in PBMC of infected individuals examined imme-
diately after isolation from peripheral blood. In particular, both STAT1 and
STAT5 were detected in the majority (70±80%) of infected individuals, re-
gardless of whether they were or not on antiretroviral therapy (Bovolenta et
al., 1999a). In addition, the predominant form of STAT5 was truncated at the
C-terminus, therefore maintaining DNA binding capacity but being devoid of
biological activity ( Bovolenta et al., 1999a); this isoform, in other cell systems,
was shown to act as a transdominant mutant for STAT5-dependent gene ex-
pression ( Bovolenta et al., 1998). Constitutive STAT activation appeared re-
stricted to CD4
T cells, allowing the speculation that both HIV particles and
gp160/120 Env molecules may be involved with this phenomenon (Fig. 14.2).
