Biology Reference
In-Depth Information
The clinical bene®ts of this restoration of immune defenses against opportu-
nistic pathogens was rapidly con®rmed by anecdotal observations of control
of opportunistic infections (Li et al., 1999) and by epidemiological surveys
( Buchbinder et al., 1999; Hogg et al., 1997; Jones et al., 1999; Pallela et al.,
1998). Indeed, the incidence of opportunistic infections in treated patients re-
covering CD4 cell numbers >200/mm
3
was similar to the incidence observed in
untreated patients <200/mm
3
(Grabar et al., 2000; Miller et al., 1999). Some
controversies still persist over the delay of reconstitution depending on the age
of patients (Chougnet et al., 1998) or the stage of the disease at which treatment
is initiated (Clerici, et al., 2000).
Some early reports mentioned, however, recurrences of CMV retinitis after
introduction of HAART (Gilquin et al., 1997; Jacobson et al., 1997). These
rare observations can be easily explained by the delay of 3 months that is usu-
ally observed between introduction of HAART and reappearance of signi®cant
immune responses to pathogens. Indeed, initiating treatment at very low CD4
counts leaves patients with a prolonged risk of opportunistic infections that can
still occur in the lag time before they reach su½cient immune reconstitution
(Miller et al., 1999). Cohort studies demonstrated very clearly that reconstitut-
ing CD4 T cells >200/mm
3
restores protection against opportunistic pathogens
and allows withdrawal of primary or secondary prophylaxis against CMV
(Jouan et al., 1999; Tural et al., 1998) and Pneumocystis carinii ( Furrer et al.,
1999; Schneider et al., 1999; Weverling et al., 1999).
These successes have some limits inasmuch as no restoration of a CD4
cell reactivity against HIV itself was observed in chronically infected patients
(Autran et al., 1997; Lederman et al., 1998; Plana et al., 1998; Pontesilli et al.,
1999; Rinaldo et al., 1999). The CD4 helper cells speci®c for HIV were restored
only when HAART was initiated at the time of primary infection (Al-Harthi et
al., 2000; Rosenberg et al., 1997, 2000). We checked that those cells were not
sequestered in the tissues ( T.S. Li, unpublished). The regeneration of new naive
CD4 cells does not help restore such activity even after 2 or 3 years of fully
suppressive treatments. However, the HIV-speci®c T-helper cells were not de-
®nitively deleted during chronic infection but persisted at very low frequencies
as shown by ¯ow cytometry studies quantifying the frequencies of HIV-p24-
speci®c CD4 T cells producing interferon (IFN )-g ( Pitcher et al., 1999). This
question of T-helper cell activity against HIV seems the most important, con-
sidering the central role played by those cells in the generation and maintenance
of the e¨ector immune defenses mediated by CTLs and antibodies (Kalams and
Walker, 1998; Matloubian et al., 1994). One of the best hallmarks of this un-
restored immunity against HIV is the rebound of uncontrolled virus replication
observed when HAART is stopped (De Jong et al., 1997; Neuman et al., 1999).
Again, only early treatment of primary infection led to some control of the
virus once the treatment is stopped ( Lisziewicz et al., 1999; Ortiz et al., 1999;
Rosenberg et al., 2000).
Such a dissociation between a strong and protective immunity rapidly re-
stored against opportunistic pathogens and a waning immunity against HIV
