Biology Reference
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e¨ects of a unique HIV-encoded or HIV-associated superantigenic determinant,
be it heterogenous or polymorphic. Furthermore, no direct evidence was pro-
vided that allowed the identi®cation of a common molecular species, HIV-
encoded or otherwise, involved in the induction of these multiple TCR reper-
toire variations. Taken together, these considerations slowly led to the demise
of the ``superantigen hypothesis.'' What then do these repertoire perturba-
tions represent? A large part of the answer came from the study of primary HIV
infection.
TCR Repertoire Analysis in Primary HIV Infection
The natural history of HIV-associated disease follows a characteristic pattern.
Shortly following infection of the host, most patients experience a febrile illness
of varying duration and severity that coincides with transient, high-level HIV-1
viremia and with a sudden decline in CD4
T-cell counts (Clark et al., 1991;
Daar et al., 1991; Tindall et al., 1989). It is during this initial phase that HIV
disseminates throughout the peripheral lymphoid organs and that long-term
viral reservoirs are established (Chun et al., 1998; Soudeyns and Pantaleo,
1999). Symptoms of primary HIV infection (PI ) subside along with the down-
regulation of viremia, which results from the appearance of host HIV-speci®c
cell-mediated immune responses (Koup et al., 1994; Musey et al., 1997; Safrit
et al., 1994). The disease then enters the so-called chronic phase, during
which HIV replication and CD4
T-cell depletion continue unabated within the
peripheral lymphoid system. To determine whether the high levels of antigen
routinely detected during PI would in¯uence the T-cell repertoire, investigators
performed TCRBV typing in a longitudinal manner in a small cohort of HIV-
infected subjects who were identi®ed prior to seroconversion. Although our
studies and those of others failed to reveal widespread deletion of speci®c T-cell
subsets (Cossarizza et al., 1995a, b), dramatic perturbations of the TCRBV
repertoire were observed, including transient high-level expansions of CD8
T
cells expressing speci®c TCRBV determinants ( Pantaleo et al., 1994). Consis-
tent with ongoing antigen-speci®c selection, these expanded populations were
comprised of one to a few T-cell clones sharing structural similarities in the
layout of the TCR b chain CDR3 loop (amino-acid sequence conservation,
focusing of CDR3 length, biased J-region usage) ( Pantaleo and Fauci, 1995;
Pantaleo et al., 1994). Accordingly, these cells bore activation markers ( HLA-
DR) and exhibited high levels of cytotoxic activity directed against autologous
targets expressing HIV-1 antigens, and therefore represented subsets of HIV-
speci®c cytotoxic T lymphocytes (CTL) that had expanded during the course of
the primary antiviral cell-mediated immune response (Pantaleo et al, 1994).
Since then, transient TCRBV-speci®c expansions of virus-speci®c CD8
T cells
have been observed during the acute stage of several other viral diseases, in-
cluding simian immunode®ciency virus (SIV ) infection (Chen et al., 1995),
measles (Mongkolsapaya et al., 1999), and infectious mononucleosis (Callan et
al., 1996). Perturbations of the CD8
T-cell repertoire were also shown to occur
