Biology Reference
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throughout the chronic phase of HIV-1 infection (Gorochov et al., 1998; Con-
nors et al., 1997). TCRBV speci®city of these T-cell expansions can be ex-
plained by the fact that, although CDR3 remains the primary determinant of
antigenic speci®city, other V-region residues and structures located outside of
CDR3 are known to be important for the recognition of Ag-MHC complexes
(Casanova et al., 1991; Garboczi et al., 1996; Garcia et al., 1998). Thus,
TCRBV restriction can be viewed as a normal result of a generalized T-cell
recruitment and expansion process associated with the emergence of primary
antiviral cell-mediated immunity.
TCR repertoire analysis was also used to examine the global mobilization of
the T-cell compartment during PI. By stratifying 30 patients according to the
number and magnitude of TCRBV-speci®c expansions observed during PI, it
was shown that the incidence and relative amplitude of these expansions were
signi®cantly correlated with the rate of CD4
T-cell decline ( Pantaleo et al.,
1997b). In addition, PI patients exhibiting single, high-level expansions of T
cells (> 10-fold over baseline) were shown to experience unusually rapid HIV
disease progression. These results con®rmed that immunological and viro-
logical events taking place during PI have a strong in¯uence on the long-term
prognosis of HIV-associated disease, and underlined the critical role of host
factors in shaping HIV pathogenesis ( Pantaleo et al., 1997b; Vanhems et al.,
2000).
Interestingly, the temporal persistence of HIV-speci®c CTL clones within
patients was shown to be quite variable, with a substantial proportion of
HIV-speci®c CTLs disappearing during PI ( Pantaleo et al., 1997a). The rapid
kinetics and completeness of this disappearance were consistent with clonal
deletion induced by high levels of viral antigens. This phenomenon was initially
described in the murine lymphocytic choriomeningitis virus (LCMV ) model,
used extensively for the study of noncytopathic viral infection (Zinkernagel,
1996). In this system, deletion of antigen-speci®c CTL expressing high-a½nity
TCRs was shown to be driven by elevated levels of antigen circulating
throughout the lymphoid compartment, and appeared to contribute to the
establishment and maintenance of viral persistence (Moskophidis et al., 1993;
Oxenius et al., 1998). In HIV-1 infection, important antigen loads are observed
throughout the duration of the disease, as viral particles are trapped and accu-
mulate within follicular dendrocyte networks ( Embretson et al., 1993; Pantaleo
et al., 1993). However, peak circulating antigen levels are reached early on
during PI, coincident with the emergence of HIV-speci®c cell-mediated immune
responses. This may very well explain why clonal exhaustion appears to occur
preferentially during PI. As discussed previously, the TCR repertoire is very
large, not in®nite, and only a limited number of peripheral T-cell clones in a
given individual can be expected to recognize a speci®c Ag/MHC combination.
In murine systems, this number has been estimated to range between 20 and
200 T-cell clones per MHC class I epitope (Maryanski et al., 1996). Therefore,
if numbers of these clones disappear early during infection, this might have a
negative impact on the long-term ability of the host to control the replication of
