Biology Reference
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the two T-cell subsets has diverted attention of AIDS biologists from the fun-
damental signi®cance of shortened telomeres in the CD8 T cells. Indeed, it is
this aspect of the AIDS telomere studies that might provide the greatest insight
into disease pathogenesis. In fact, although unbeknown to the community of
AIDS researchers, cell biologists interested in the mechanisms controlling cell
cycle arrest, telomere regulation, and the Hay¯ick Limit view HIV disease as
the most dramatic example to date of the in vivo pathophysiologic relevance of
the process of replicative senescence.
Our own telomere studies were, in fact, originally initiated to speci®cally test
whether replicative senescence might be occurring during HIV disease. We had
already documented T-cell telomere shortening during aging, had identi®ed
loss of CD28 expression as a marker of replicative senescence in vitro, and had
reported age-related increase in the proportion of CD8 T cells lacking CD28
expression ( Boucher et al., 1998; E¨ros et al., 1994a; Vaziri et al., 1993). In-
terestingly, it has been recently suggested that loss of CD28 expression in vivo
might be a marker of chronic/latent infection, based on the correlation of in-
creased proportions of CD28
ÿ
T cells with chronic CMV infection ( Looney et
al., 1999; Weekes et al., 1999b). High proportions of CD28
ÿ
T cells had been
documented in HIV-infected individuals, but their origin and signi®cance were
unclear (Borthwick et al., 1994; Brinchmann et al., 1994; Jennings et al., 1994;
Lewis et al., 1994). When we compared telomere lengths in sorted populations
of CD28
CD8
and CD28
ÿ
CD8
T cells obtained from individual HIV-
infected donors, we found that the telomere length of the CD28
ÿ
CD8
T-cell
subset had shortened to a size of 5±7 kb, which is identical to that of T cells that
have undergone multiple rounds of antigen-driven proliferation in cell culture
to reach replicative senescence ( E¨ros et al., 1996). Moreover, within individual
donors, the proportion of CD28
ÿ
T cells increases progressively over time. Be-
cause T cells lacking CD28 are nonproliferative in response to anti-CD3 anti-
bodies plus IL-2 (Azuma et al., 1993) or phorbol myristic acetate/ionomicin
plus IL-2 ( E¨ros et al., 1996), our ®ndings supported the hypothesis that repli-
cative senescence might be a feature of HIV disease pathogenesis.
The demonstration of extensive CD8 T-cell division possibly leading to the
irreversible state of replicative senescence in HIV disease builds on an increas-
ing body of evidence suggesting a crucial role for CD8 T cells in both the pri-
mary acute response as well during disease progression. Giorgi and others have
demonstrated that cellular markers of immune activation, especially increased
expression of CD38 and HLA-DR on the surface of CD8 T cells, accompany,
re¯ect, and predict disease progression. (Cossarizza et al., 1995; Giorgi et
al., 1994, 1999; Ho et al., 1993; Kaufmann et al., 1999; Zaunders et al., 1999).
Diminished expression of CD38, correlating with increased proportions of
CD28
T cells and increased proliferative capacity, has been documented in
patients receiving long-term highly active antiretroviral therapy (HAART )
(Carcelain et al., 1999; Sndergaard et al., 1999), suggesting that CD28 expres-
sion may be an important marker of immune function. In this regard, it is be-
coming increasingly clear that the combination of immunological and virologic
