Biology Reference
In-Depth Information
1998). Indeed, compared with healthy donors, a signi®cant decrease in the fre-
quency of T cells primed for IL-2 or TNF-a was observed, whereas that of
T cells primed for IFN-g was unchanged. The disappearance of IL-2-producing
T cells in HIV-infected persons appeared to be a good indicator of disease
progression and to correlate with the progressive shrinkage of the naive
CD45RA
CD4
T-cell compartment, the main producer of IL-2 ( Ledru et al.,
1998).
Analysis of the priming for apoptosis of T-helper-cell subsets revealed that
the intrinsic capacity of lymphocytes to produce a given cytokine can in¯uence
their survival ( Ledru et al., 1998). Indeed, T lymphocytes committed to IFN-g
or TNF-a production are more sensitive to activation-induced apoptosis than
lymphocytes committed to IL-2 production. This gradient of susceptibility to
apoptosis ( IL-2 < IFN-g < TNF-a) was detected in both CD4 and CD8 T-cell
subsets, both in control donors and HIV-infected patients, in whom the sus-
ceptibility to apoptosis of IL-2 and TNF-a producers was increased compared
with controls. In addition, this di¨erential intrinsic susceptibility to apoptosis of
Th1 e¨ectors is tightly regulated by Bcl-2 expression. In HIV-infected persons,
the progressive decrease in the proportion of IL-2-producing T cells is cor-
related with their susceptibility to apoptosis and disease progression. On the
other hand, the frequency of IFN-g producers is preserved in patients despite
an increased rate of apoptosis in this subset, which is counterbalanced by an
increased proportion of CD45R0
CD8 T cells', the main IFN-g producers,
survival (Ledru et al., 1998). Altogether, these observations indicate the im-
portant relationship between increased priming for apoptosis in peripheral T
cells, alteration in cytokine synthesis, and disease evolution.
IMPACT OF HAART ON T-CELL HOMEOSTASIS AND IMMUNE
RESTORATION
HAART Regulates Lymphocyte Apoptosis
Antiviral therapy for HIV-infected patients has greatly improved in the recent
years, and administration of HAART, combining HIV reverse transcriptase
( RTIs) and protease inhibitors (PIs), has been successful in decreasing plasma
viremia to undetectable levels, and dramatically changed the clinical course in a
substantial proportion of patients (Flexner, 1998). However, the use of these
combinations for prolonged periods of time is not without drawbacks, such
as adherence to complex drugs regimen, risks of side e¨ects, and viral resis-
tance. Furthermore, di¨erent groups demonstrated that the pool of latently in-
fected cells persists in essentially all infected patients tested who were receiving
HAART for a long period of time (up to 3 years) and in whom suppression of
plasma viremia has been maintained below the levels of detection by the most
sensitive assays (Finzi et al., 1999, Zhang et al., 1999).
These potent therapies have challenged the question of the mechanisms
