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by strong slopes of peripheral blood CD4 T cells of 1±5 CD4 cells/mm
3
/day
during the ®rst 2 months of treatment (Fig. 20.1A) concurrently with a rapid
and major reduction in virus load of 1 or 2 log of magnitude (Fig. 20.1B).
Various other studies con®rmed those ®rst results, both on peripheral blood
cells ( Lederman et al., 1998; Pakker et al., 1998; Pontesilli et al., 1999; Rinaldo
et al., 1999) and on lymph nodes (Bucy et al., 1999; Cavert et al., 1997; Fleury
et al., 1998; Sachsenberg et al., 1998; Tenner-Racz et al., 1998; Zanussi et al.,
1999). Such ®ndings suggested that the CD4 and CD8 T cells had been pre-
viously recruited in lymphoid tissues at the time of active virus replication
where they had been sequestered in an altered cytokine and chemokine milieu
(Cheynier et al., 1994; Rosok et al., 1996). The arrest of local virus production
(Cavert et al., 1997; Patki et al., 1999; Wong et al., 1997) in lymphoid tissues
should allow the sequestered T cells to recirculate ( Bucy et al., 1999), thereby
increasing peripheral blood cell counts. Similar phenomena are observed at any
stage of the CD4 cell depletion, that is, from primary infection to full-blown
AIDS (Carcelain et al., 1999). However, such CD4 cell mobilization substan-
tially increases peripheral blood cell numbers, mostly in patients with low CD4
counts. Thus, no massive gain in the total CD4 cell compartment occurs at this
early phase of immune reconstitution.
What are the factors in¯uencing such early rises in CD4 counts? We dem-
onstrated that the ®rst-phase CD4
T-cell slope is positively correlated with the
baseline CD4 count, and even more strongly but negatively correlated with the
slope of CD4
T-cell decline during the year prior to PI initiation ( Renaud et
al., 1999). This relation with prior CD4
T-cell decline was also observed
among the patients with a prolonged history of major CD4
T-cell depletion
(<50/mm
3
) and those with higher CD4 counts and slow disease progression
before study entry (data not shown). On the other hand, age and amplitude of
viral load reduction over a 2-month period had low e¨ects on the early CD4
T-cell recovery, whereas baseline viral load values had no signi®cant impact
( Renaud et al., 1999).
The kinetics of the CD4 cell expansion are usually reduced after the second
or third month of treatment (Fig. 20.1B) (Autran et al., 1997; Connick et al.,
2000; Fleury et al., 2000; Pakker et al., 1998). The slopes of CD4 recovery are
usually 1 log lower than during the ®rst 2 months. This second phase of im-
mune reconstitution seems to be strongly correlated with the magnitude of the
plasma viral load reduction and its stability over time (Fig. 20.1B) (Connick
et al., 2000; Renaud et al., 1999). Indeed, a 4 log reduction in the plasma viral
load can be associated with a 40% increment slope during the 2 years following
HAART initiation whereas a 1 log viral load reduction is usually associated
with a 5% slope only (Fig. 20.1B). Thus, stable control of the HIV replication
allows a steady and continuous increase in CD4 counts. A variation of the
mean viral load of ÿ1 log
10
HIV-RNA copies/ml between month 2 and month
24 in two otherwise identical patients meant that their second-phase CD4
T-cell slope di¨ered by 0:11 CD4/mm
3
/day. These ®ndings suggest that, when
