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intracellular markers associated with cell cycle, such as Ki67, was reported in
CD4 T cells as an inverse correlation of the CD4 cell depletion (Fleury et al.,
1998; Lempicki et al., 2000; Orendi et al., 1998; Sachsenberg et al., 1998;
Tenner-Racz et al., 1998). Little evidence could support, however, the hypoth-
esis of a high replacement rate. Indeed, telomeres were shown to maintain a
subnormal length in CD4 T cells (Wolthers et al., 1996). We demonstrated that
Ki67 was not associated with mitosis in memory CD4 T cells from HIV-
infected patients but only with entry in the G1 phase of the cell cycle and
T-helper cell activity (CombadiÁre et al., 2000). Finally, no increased incorpo-
ration of BrdU could be detected by ex vivo ¯ow cytometry in CD4 T cells
from HIV-infected patients (Tissot et al., 1998). Thus, the increased expression
of Ki67 re¯ects massive mobilization of activated memory or e¨ector CD4 T
cells during a chronic virus infection rather than a massive enhancement of the
CD4 cell turnover (CombadiÁre et al., 2000). Nevertheless, increased incorpo-
ration of deuterated glucose in CD4 T cells could be related to a three-fold
increase of the CD4 T cell turnover ( Hellerstein et al., 1999), which was com-
patible with Ki67 and telomere data (Fleury et al., 1998). In addition, bone
marrow progenitor production (Marandin et al., 1996) and thymic T-cell pro-
duction ( Bonyhadi et al., 1993) were shown to decrease during HIV disease
progression, although the thymic mass does not decrease signi®cantly (McCune
et al., 1998). This low replacement rate together with an enhanced conversion
rate of naive-to-memory CD4 T cells due to the intense immune activation
ultimately leads to naive T cell depletion ( Roederer 96, Herzenberg 2000).
Normalizing these phenotypes and functions with antiretroviral drugs thus
represented a major challenge to the medical and scienti®c community. Flow
cytometry helped to rapidly demonstrate the capacity of the CD4 T-cell com-
partment to reconstitute in HIV-infected patients together with the kinetics and
mechanisms of such reconstitution.
THE DYNAMICS OF CD4 CELL RECONSTITUTION:
A TWO-PHASE PROCESS
New antiretroviral drug regimens combining inhibitors of two HIV enzymes,
the reverse transcriptase ( RTI ) and the protease (PI ) opened in 1995 a new era
by inducing major and stable reduction in viral load accompanied by sustained
CD4 cell increases (Collier et al., 1996; Gulick et al., 1997; Hammer et al.,
1996; Katzenstein et al., 1996) that had never been previously reported with
mono- or bi-therapy with RTI. Such changes immediately raised the question
of immune restoration and its mechanisms.
Our group conducted, in 1996, the ®rst study evaluating the consequences of
HAART on the various T-cell alterations brie¯y summarized above (Autran
et al., 1997). Patients, naive of any antiretroviral drugs, were treated with one
PI and two nucleoside analogs at a late stage of the CD4 depletion with CD4
counts <250/mm
3
. A very early increase in CD4 counts was characterized
