Immunotherapy for Infectious Diseases

184 Kalams
complexed with HLA class II molecules. T-helper epitopes are typically larger than
HLA class 1-restricted epitopes, in the 12–17-amino acid range. They are presented via
the exogenous antigen pathway and complexed with HLA class II molecules at the cell
surface, where they are recognized by CD4� T-cells. It is not known exactly what constitutes
help, but it is probably composed of released lymphokines and a series of direct
cell-cell interactions. The critical role of T-helper cells in response to chronic viral
infection has been firmly demonstrated in animal models. For example, after LCMV
infection of mice, an LCMV-specific CTL response develops that controls viremia.
However, in the absence of CD4� T-cells, either because of genetic knockout or
antibody-mediated depletion, the CTL response cannot be maintained and results in
persistent viremia (40–42). In contrast to other infections such as cytomegalovirus
(CMV), helper responses in HIV-1 infection are typically low or absent in the presence
of persistent viremia.
Cross-sectional studies of subjects with wide ranges of viral loads have demonstrated
a negative correlation between HIV-1 Gag-specific helper responses and viral
load (43–46). In addition, helper responses are also positively correlated with the magnitude
of HIV-1-specific CTL responses (44), further demonstrating that both responses
are likely to be important for immune-mediated control of viral replication. The identification
and immunologic characterization of subjects with long-term control of HIV
replication demonstrates that immune control of HIV is possible, and these subjects
typically have robust HIV-specific CTL and helper responses (47,48). These findings
suggest that the combination of strong helper and CTL responses is required for control
of viremia during HIV infection.
FACTORS LEADING TO LOSS OF CONTROL OF VIREMIA
Immune Exhaustion
A number of longitudinal studies have demonstrated that CTL responses decline
with disease progression (49–52) and that this decline is probably related to the frequent
absence of HIV-1-specific helper responses in infected individuals (52). Immune
exhaustion, defined as a disappearance of antigen-specific CTL clones, has been postulated
to occur because of sustained high-level viremia. Animal models suggested that
CTL could expand maximally and then be deleted in the presence of a high viral load
(53). Early studies of V� TCR subsets in humans suggested this might also be the case
in HIV infection (54). However, more recent studies evaluating antigen-specific CTL
clones have demonstrated the persistence of these cells in the face of a high antigen
load (55,56). If the defect is not the absence of CTL clones, but rather a lack of function,
or a lack of ability to expand in the presence of antigen, these more recent data
suggest that efforts to augment these responses could prove beneficial.
This inability to maintain CTL function, despite the physical presence of CTL clones,
may be related to inadequate T-helper cell function. More recent studies in LCMV infection
show that although deletion of CTLs is possible, the persistence of virus can more
often be explained by a silenced phenotype of CTLs that are present (as defined by
tetramer staining) but unable to secrete IFN-� in response to antigenic stimulation (5,6).
Although this hypothesis has not yet been confirmed in the setting of HIV-1-infection,
it suggests that efforts to restore helper function may increase CTL function.