Biology Reference
In-Depth Information
the redistribution phenomenon is over, the immune system is repopulated at the
same pace in most cases, whatever the severity of the immune alterations that
had taken place before introduction of HAART.
Such progressive and virus-dependent reconstitution brings the CD4 counts
above the symbolic threshold of 200/mm 3 within 12±24 months in very severe
stages of the disease, thus ensuring protection against opportunistic pathogens.
Normal or subnormal CD4 values can then be reached within 2±4 years, de-
pending ®rst on the disease stage at which treatment had been initiated and
second on the persistent control of the virus replication ( Fleury et al., 2000;
Mezzaroma et al., 1999; Renaud et al., 1999; Schooley, 1999; Weiss). Thus,
most protection will be more rapidly attained when HAART is introduced at
early stages than at end stages of the CD4 cell depletion (Miller et al., 1999).
In some patients, however, CD4 count reconstitution seems to be indepen-
dent of virus control. This phenomenon was ®rst reported in a Swiss cohort
( Kaufman et al., 1998) followed by several groups ( Levitz, 1998; Piketty et al.,
1998). We observed similar phenomena in a group of 320 patients followed in
our institution (Renaud et al., 1999). Two di¨erent paradoxical patterns were
detected at 2 months of therapy. Paradoxical CD4 nonresponders were de®ned
as having a viral load reduction >1 log 10 but no CD4 T-cell increase from
baseline. In these cases (8%), the median slope of initial CD4 recovery was
ÿ0:26 CD4 T cells/mm 3 /day. On the other hand, paradoxical CD4 responders
at month 2 were de®ned as having a lack of signi®cant reduction in HIV-RNA
copies/ml (<0.5 log 10 ) but a CD4 count increase from baseline >50 CD4 cells/
mm 3 (which was the median CD4 gain at month 2 for all study patients). In
these cases (7%), the median ®rst-phase slope was 1:5CD4 T cells/mm 3 /day.
The low in¯uence of viral load reduction during the ®rst phase of rapid CD4
increase and its strong in¯uence over the long term explain the paradoxical
CD4 responses reported by others. Indeed, a simple mathematical model helps
explain how a minimal virus load reduction is enough to generate some redis-
tribution from the tissues ( Drusano and Stein, 1998). However, the absence
of signi®cant CD4 decline observed over the long term in paradoxical CD4
responders still contrasts with the lack of virus control and cannot be fully
explained by the factors described herein. Although we could not isolate age
as an important parameter, it certainly plays a role in delaying or impairing
thymic regeneration (McCune et al., 1998, 2000; Smith et al., 2000)
NAIVE AND MEMORY CD4 T CELLS ARE THE ACTORS OF THE
CD4 CELL RECONSTITUTION
Simple ¯ow cytometry analyses helped demonstrate the mechanisms of such
CD4 T-cell reconstitution (Fig. 20.1A). In our ®rst study, the rapid early wave
of CD4 T cells was shown to be mostly composed of memory CD4 T cells
bearing the CD45RO isoform. Pakker and colleagues con®rmed this early rise
in memory T cells, supporting the hypothesis of a cell redistribution from the
Search WWH ::




Custom Search