Biology Reference
In-Depth Information
produce soluble antiviral factors, generate su½cient antioxidants, and tra½c
normally into the tissues will undoubtedly diminish the quality of the protective
immune response. Admittedly, it is possible to argue that the above charac-
teriistics, rather than being abnormal, re¯ect the evolution of a mature immune
response. Namely that the CD28
CTL precursors ®rst proliferate and secrete
antiviral factors, and, as they divide, an increasing proportion of cells lose
CD28 expression, have shortened telomeres, and the amount of antiviral fac-
tors decreases as the cytotoxicity is enhanced and reaches its peak at the point
at which the CD8 T cells can no longer undergo proliferation. This alternative
scenario, however, seems less likely, inasmuch as the increase in the proportion
of CD28
ÿ
T cells correlates with disease progression and ultimate loss of con-
trol over the infection. More detailed elucidation of what seem to be discrete
stages CD8 T-cell e¨ector cell progression in HIV-infected persons seem to be
emerging from approaches using additional markers such as CD27 and CD57
to more precisely de®ne CD8 T-cell function and cytokine pro®les (Appay et
al., 2000; Lewis et al., 1999). Such analyses will provide more detailed under-
standing of the biology of CD8 T cells during chronic infection and their pre-
cise contribution to HIV disease pathogenesis.
Irrespective of the speci®c mechanism responsible for the progressive in-
crease in the proportion of CD28
ÿ
CD8
T cells in HIV-infected persons, the
physical presence of this substantial population will undoubtedly in¯uence
homeostatic processes that control the size and components of the peripheral
T-cell pool (Caruso et al., 1998; Freitas et al., 1996; Rocha et al., 1989). What is
already clear from studies on elderly people not infected with HIV is that an
increased proportion of CD8 T cells lacking CD28 is associated with reduced
numbers of na
È
ve CD8 T cells (Fagnoni et al., 2000), indicating a possible
negative feedback regulatory mechanism that is subset speci®c. Moreover, in
HIV-infected persons, several groups have documented an inverse correla-
tion between numbers of CD28
ÿ
CD8
and CD4 T cells (Caruso et al., 1998;
Choremi-Papadopoulou et al., 2000; Lewis et al., 1999). In this regard, it is
possible, for example, that the removal of some of the CD28
ÿ
CD8
T cells
might serve as a stimulus for the production of more functional antigen-speci®c
CD8 T cells, and possibly even new CD4 T cells. Although it is highly unlikely
that current antiretroviral treatment regimens will reverse telomere shortening
and loss of CD28 expression in individual cells, use of these drugs in combina-
tion with the physical removal of senescent cells may prevent a recurrence of
the excessive telomere shortening, replicative senescence, and loss of CD28.
Antiretroviral therpay is, in fact, associated with the reconstitution of the lym-
phoid compartment with cells having longer telomeres, indicative of increased
replicative potential ( Kaushal et al., 1999). Early implementation of anti-
retroviral therapy may also prevent the telomerase inhibition observed in bone
marrow stem cells of HIV-infected persons (Vignoli et al., 1998), a process that
may be further accelerating the disease progression and immune collapse.
The development of new treatment approaches for HIV disease can also
be profoundly in¯uenced by increased understanding of the nature of the
