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sive accumulation of both CD4 and CD8 T cells primed for TNF-a synthesis
is detected in the blood of treated patients ( Fig. 12.3A) (Ledru et al., 2000).
Because apoptosis plays an essential role in the negative regulation of TNF-a
synthesis by T cells ( Ledru et al., 1998), and apoptosis is suppressed under
HAART, we combined the detection of apoptosis with that of cytokine syn-
thesis on patients' T cells in order to analyze the relationship between both
processes. As shown in Figure 12.3B, the accumulation of TNF-a T-cell pro-
ducers under HAART is correlated with the suppression of physiological
apoptosis in this subset. This is partly related to the cosynthesis by TNF-a T-
cell producers of IL-2, an antiapoptotic factor ( Ledru et al., 2000). In addition,
the possible in vivo antiapoptotic in¯uence of PI, by a direct e¨ect on cellular
proteases (Sloand et al., 1999), may contribute to the accumulation of TNF-a T-
cell producers. Therefore, the re-emergence of CD4 T cells consequent to neu-
tralization of HIV by HAART is not associated with the complete restoration of
cytokine synthesis. Moreover, recent studies have shown that HIV-speci®c CD4
and CD8 responses, which may contribute to the containment of HIV replication
(Ortiz, 1999; Schmitz, 1999) decline during HAART and become undetectable
( Pitcher et al., 1998). More studies are needed to evaluate the renewal capacities
of the immune system when HIV replication is controlled.
HAART-Associated Lipodystrophy Syndrome: Relation with Hormonal
and Cytokine Dysfunctions
Long-term HAART has been associated with a unique and unexpected syn-
drome consisting of alterations in lipid metabolism and body fat redistribution,
also called lipodystrophy. Lipodystrophy ( LD) is associated with hyperlipidemia,
insulin resistance, peripheral loss of fatty tissue, and visceral abdominal fat ac-
cumulation (Carr et al., 1998). The pathogenesis of this syndrome, which may
lead to premature coronary artery disease as recently reported in PI-treated
HIV-infected patients, remains unknown. Because important hormonal alter-
ations, such as increased androgen and cortisol levels, were reported in chroni-
cally HIV-infected patients (Christe¨ et al., 1997) and considering that lipid
metabolism is under the control of glucocorticoids, androgens, and cytokines,
we asked whether peripheral LD is related to hormonal and immunological
dysfunctions. We found that increased atherogenic lipids associated with LD
are also associated with increased cortisol, decreased DHEA serum levels, and
consequently increased cortisol/DHEA ratio in HAART-treated LD
vs. LD
ÿ
patients (Christe¨ et al., 1999). In LD
patients, elevated cortisol will stimulate
peripheral adipocyte lipolysis. In parallel, because of the direct e¨ect of DHEA
on lipoprotein lipase activity and on peripheral insulin resistance, the decrease
in DHEA in LD
patients may contribute to the reduction in peripheral lipo-
genesis. Thus, the combined DHEA decrease and elevated cortisol in LD
patients is probably responsible for the imbalance between lypolysis and lipo-
genesis in the peripheral adipose tissues.
Cytokines, such as TNF-a, induce a number of alterations in lipid metabo-
