Biology Reference
In-Depth Information
Cell surface molecules related to T-cell activation function also progressively
normalize. The CD28 coactivation molecule, down-modulation of which
during the course of the disease contributes to cell anergy and sensitivity to
apoptosis, reaches a full expression on 99% of CD4 cells during treatment of
both primary and chronic HIV infection (Autran et al., 1997; Carcelain et al.,
1999). In addition, the subset of CD4 cells that lacks the CD7 molecule and
mediates a Th0/Th2 function slowly decreases and reaches normal values below
10% of the CD4 compartment after a year of successful therapy (unpublished
observations).
Altogether, reduction in abnormal immune activation might be one of the
key phenomena that allows, or at least contributes to, quantitative and func-
tional immune reconstitution. Indeed, as discussed above, reducing the abnor-
mal immune activation and losses in the memory T-cell compartment prolongs
their survival, reduces the consumption of naive T cells, and helps restore their
numbers (Hazenberg et al., 2000a, 2000b) while facilitating recirculation of the
CD4 T-cell subset. Thus, antiretroviral drugs, by blocking virus production,
reduce the virus-driven immune activation and play a potent anti-in¯ammatory
role in the immune system. Overall, such anti-in¯ammatory e¨ects might be
even as important as thymic production for immune recovery.
RECONSTITUTION OF HOST DEFENSES DURING HAART:
SUCCESSES AND LIMITATIONS
One of the major questions raised by physicians and patients was whether re-
storing CD4 cell numbers and homeostasis would restore the defenses that had
been lost with AIDS. The phenotypic improvements reported above strongly
suggested that the functional defects in memory T cells would also be corrected.
Indeed, T-cell function studies rapidly showed that CD4 T-cell responses
against cytomegalovirus (CMV ) and mycobacterium tuberculosis were shown
to be restored after 3 months of HAART in AIDS patients (Autran et al., 1997;
Lederman et al., 1998; Li et al., 1998; Pontesilli et al., 1999; Rinaldo et al.,
1999; Valdez et al., 2000). Such reconstitution appears concurrently with
memory CD4 cell increase and normalization of the in¯ammatory syndrome
and requires a solid and durable control of HIV replication (Li et al., 1998;
Wendland et al., 1999). Blocking HIV replication for only 3±6 months was not
enough to restore a CMV or a tuberculin-speci®c immunity ( Li et al., 1998).
The classical T-cell proliferation assays are, however, poorly quantitative and
could not assess increases in antigen-speci®c CD4 T-cell numbers. New ¯ow
cytometry analyses of the intracellular production of cytokines upon antigen
stimulation helped demonstrate a quantitative restoration of CMV-speci®c
CD4 T cells ( Komanduri et al., 1998). These new methods clearly demon-
strated an expansion in the frequencies of CMV-speci®c CD4 T cells that
strongly correlated with the improved CMV disease status after introduction of
HAART.
