Biology Reference
In-Depth Information
controlling homeostasis and reconstitution of the immune system in treated
patients, and recent studies have pointed out the complexity of the mechanisms
involved. The increase in CD4 T cells after HAART results from a combina-
tion of release of sequestered cells from lymphoid compartments to peripheral
blood (Pakker et al., 1998), increased production rate of circulating T lym-
phocytes due to peripheral T-cell expansion ( Fleury et al., 1998; Hellerstein et
al., 1999), suppression of apoptosis (Gougeon et al., 1999) and central produc-
tion of new T cells ( Douek et al., 1998), suggesting that the mechanisms of
renewal of CD4 T cells are still operational in chronically infected patients.
Rapidly after initiation of HAART, an important drop in spontaneous and
activation- and CD95-triggered apoptosis is observed in both CD4 and CD8
T cells from treated patients. This generally occurs before the decrease in
the expression of activation markers CD45R0, HLA-DR, and CD95, but 6
months post-therapy both T-cell apoptosis and immune activation are sup-
pressed, reaching control values (Gougeon et al., 1999; Sloand et al., 1999).
This is shown in three representative patients in Figure 12.2A. In addition,
suppression of the intrinsic fragility of patients' T cells under antiretroviral
therapy is associated with normalization of the survival rate of activated lym-
phocytes, as shown in Figure 12.2B in an 18-month longitudinal study of three
patients under HAART. Thus, potent inhibition of HIV replication is asso-
ciated with normalization of lymphocyte apoptosis, and it is probably a multi-
factorial process. Indeed, mechanisms involved in apoptosis susceptibility of
patients' lymphocytes during the chronic phase of HIV infection, i.e., in vivo
immune activation and proapoptotic e¨ect of some HIV proteins, are down-
regulated under HAART, restoring the survival of patients' lymphocytes. but
we cannot exclude a direct in vivo immunomodulatory e¨ect on T cells of anti-
HIV drugs, including PIs, some of them being recently shown to suppress in
vitro physiological apoptosis by inhibition of cellular proteases (Sloand et al.,
1999). However, the inhibitory e¨ect of HAART on ex vivo CD95- or anti-
TNF-R-induced apoptosis is not observed in all the patients, in spite of good
immunological (increased CD4 count) and virological (suppressed viral load)
responses. Indeed, we have recently observed that certain antiretroviral drug
regimens do not control both ex vivo spontaneous and activation-induced T-
cell apoptosis, and, although it is not related to the viral load, it is correlated
with the CD4/CD8 ratio and the type of RTI used (L. de Oliveira Pinto et al.,
unpublished data).
Partial Restoration of IL-2 Synthesis and Alteration of TNF-
a
T-cell
Homeostasis Under HAART
As discussed above, we have shown that chronic HIV infection is associated
with an altered pattern of Th1 subsets, characterized by a progressive decrease
in the number of IL-2 and TNF-a producers, which was correlated with their
increased priming for apoptosis. Because the level of lymphocyte apoptosis
is normalized under HAART, we asked whether these potent therapies could
