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that has been registered in all industrialized countries ( Buchbinder et al., 1999;
Hogg et al., 1997; Pallela et al., 1998). The immune reconstitution obtained
with these antiretroviral drugs, even if incomplete, has produced de®nitive evi-
dence for the central role played by HIV itself in the massive alterations of the
immune system. Intense publishing activity followed the ®rst descriptions of
immune reconstitution with antiretroviral therapy, illustrating the enthusiasm
and the controversies raised by these observations.
We will review the major quantitative, qualitative, and functional charac-
teristics of the CD4 T-cell reconstitution together with its limitations and the
new insights that recently developed ¯ow cytometry methods have brought to
the understanding of such CD4 T-cell reconstitution.
THE CD4 T CELL COMPARTMENT IN THE PRE-HAART ERA OF THE
HIV INFECTION
The CD4 T-cell depletion results from a direct pathogenicity of HIV and/or
from the cytolysis mediated by cytotoxic T lymphocytes (CTL) against the in-
fected CD4 cells that actively replicate the virus. ``Innocent'' non-HIV-infected
CD4 T cells also die in excess during the course of the natural infection due to a
major activation of the immune system that results in an enhanced activation-
induced cell death. The peripheral blood CD4 cells re¯ect, however, only 2% of
the total body CD4 compartment. The severity of the CD4 cell loss in lymphoid
tissues might not be as severe, however, as suggested by peripheral blood
counts, because CD4 cells might be sequestered in the lymphoid organs during
the natural course of the disease ( Rosok et al., 1996). Losses mainly a¨ect the
activated memory CD4 T cells, which can be operationally de®ned by the cell
surface co-expression of the CD45RO isoform. Various markers of T-cell acti-
vation, such as CD25, human leukocyte antigen ( HLA)-DR, CD38, or Fas
( Badley et al., 1998; Giorgi et al., 1997) are abnormally expressed on those cells
as a correlate of disease progression and plasma HIV load, whereas some
markers associated with T-cell competence and T-helper di¨erentiation, such as
CD28 and CD7 ( Borthwick et al., 1994; Autran 1996), have a decreased ex-
pression. Memory T-cell function defects are assessed by a progressive loss in
proliferative capacity, interleukin (IL)-2 production, and T-helper-1 cell reac-
tivity against various recall antigens and opportunistic pathogens (Clerici et al.,
1989; Lane et al., 1985). A major controversy was raised as to whether the
turnover of peripheral mature CD4 T cells was enhanced ( Hellerstein and
McCune, 1997; Hellerstein et al., 1998; Ho et al., 1995; Perelson et al., 1996;
Wei et al., 1995; Wolthers et al., 1996). According to the tap and drain hy-
pothesis (Ho et al., 1995; Perelson et al., 1996), an increased CD4 cell prolifer-
ation should compensate cell losses at early stages of the disease and should
become detectable during the rapid increase of CD4 counts that follows thera-
peutic reduction of viral replication. Flow cytometry analyses helped provide
rough data to support or reject such a hypothesis. An increased expression of
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