Biology Reference
In-Depth Information
CD4 T cells are either killed or undergo apoptosis and are replaced by thymus-
derived naÈve cells, the longer telomere lengths of the naÈve cells may obscure
any CD4 T-cell shortening that might have occurred among memory CD4 T
cells. E¨orts aimed at optimizing Flow-FISH telomere analysis will ultimately
clarify these issues.
The potential involvement of telomerase in the di¨erent telomere length dy-
namics of CD4 and CD8 T cells provides another possible explanation for the
observations in HIV-infected individuals. Telomerase, the enzyme that extends
telomere sequences, might function to retard or prevent telomere shortening in
CD4 T cells. Although no di¨erences in baseline or inducible telomerase levels
were detected in vitro between CD4 and CD8 T cells during the chronic stage
of infection ( E¨ros et al., 1996; Wolthers et al., 1996, 1999), these ®ndings do
not preclude possible in vivo involvement of telomerase activity at an earlier
time-point in the disease process. Telomere length maintenance is, in fact, ob-
served in human T cells in cell culture during the period that coincides with
high telomerase activity (Bodnar et al., 1996). Similarly, a study on the kinetics
of telomerase induction in vivo during the very early stage of Epstein-Barr virus
( EBV ) infection shows that high telomerase activity is present in antigen-
speci®c T cells during acute infectious mononucleosis and correlates with elon-
gation of telomeres in these cells (Maini et al., 1999). This study suggests that
telomere-lengthening mechanisms can operate in vivo during the early stages
of infection and that there is apparent lengthening within the population of T
cells that is undergoing massive clonal expansion. Germinal center B cells with
elongated telomeres have also been reported (Weng et al., 1997a). Thus, results
from other experimental systems are consistent with the possibility that CD4 T
cells in HIV-infected persons have indeed undergone a greater number of cell
divisions than is re¯ected in their telomere length.
In any event, whatever factors contribute to the absence of the expected
telomere shortening in the CD4 subset, one should not dismiss the importance
of the dramatic and progressive telomere shortening in CD8 T cells, the subset
responsible for e¨ective immune control over the virus. More importantly, be-
cause telomere length is, in general, predictive of a cell's overall proliferative
potential (Harley et al., 1990), the telomere studies on HIV-infected persons
document the presence of a population of CD8 T cells that is severely com-
promised in its ability to undergo further clonal expansion. In addition, the
high proportion of CD28
ÿ
T cells will clearly reduce a critical component
antiviral e¨ector function, because antiviral suppressive factor production is
restricted to CD8 T cells that are CD28
(Landay et al., 1993).
TELOMERE STUDIES AND HIV PATHOGENESIS
As discussed above, the absence of telomere shortening in CD4 T cells has nu-
merous potential explanations. Unfortunately, the substantial e¨ort expended
on the analysis and debate regarding di¨erences in telomere dynamics between
