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changes do not correlate with markers of disease progression. Preliminary evi-
dence from two studies had suggested that CD4 telomere shortening might occur
at late stage disease ( E¨ros et al., 1996; Pommier et al., 1997). However, in a
subsequent more extensive analysis of TRF in PBMC versus CD4 T cells, both
increases and decreases of CD4 T-cell telomeres were observed, with no correla-
tion between CD4 T-cell telomere length changes and other well-established
markers of disease status, such as CD4 counts and CD8
CD38
T cells (E¨ros,
Giorgi, Valenzuela, and Mitsuyasu, manuscript in preparation).
DIVERGENT TELOMERE DYNAMICS BETWEEN CD8 AND
CD4 T CELLS IN HIV-INFECTED PERSONS
Telomere measurement, at best, can only provide information on the replicative
history and the long-term total replicative potential of a cell population, but
is not the most appropriate assay for studying overall population dynamics,
half-life, or rate of replacement of T cells in HIV disease. Thus, the marked
divergence in the telomere ®ndings between CD8 and CD4 T cells need not be
interpreted as being at odds with the cell turnover studies, but rather as further
demonstration of the restricted information that can be derived from telomere
length measurement. Indeed, cell turnover studies that measure the rate of cell
division have clearly demonstrated quite similar rates for both T-cell subsets.
For example, equivalently high turnover in both CD4 and CD8 T cells from
HIV-infected persons has been determined by analysis of the mutation fre-
quency at the hypoxanthine phosphoribosyltransferase ( HPRT ) locus (Paganin
et al., 1997) and in bromodeoxyuridine labeling studies on simian immuno-
de®ciency virus-infected rhesus macaques (Mohri et al., 1998; Rosenzweig et
al., 1998). Thus, the extraordinarily high turnover rate of CD4 T cells, a notion
based on the rebound of CD4 T-cell number during antiretroviral therapy (Ho
et al., 1995; Wei et al., 1995), need not necessarily involve telomere shorten-
ing and, therefore, the telomere length ®ndings do not con¯ict with studies
measuring repopulation, replacement, or rate of cell division. Moreover, in the
absence of telomere data on speci®c CD4 T-cell subpopulations de®ned by
phenotypic markers, precise conclusions from telomere studies are impossible.
Finally, even research involving clonal populations of T cells propagated in
vitro indicates that the unconditional use of telomere length data to assess
turnover of lymphocytes may be lead to incorrect conclusions (Rufer et al.,
1998).
The divergence in observed telomere shortening patterns between CD4 and
CD8 T cells, therefore, most probably re¯ects the disparate roles of the T-cell
subsets during HIV disease rather than any inherent limitations of the tech-
nique of telomere analysis itself ( Hellerstein and McCune, 1997; Rosenzweig et
al., 1998). Because CD4 T cells are targets of HIV, it seems likely that those
cells that become infected by HIV undergo only a few cell divisions before
dying by apoptosis or being lysed by CTL, thereby limiting the time frame
during which telomere shortening can occur. Alternatively, when activated
