Immunotherapy for Infectious Diseases

188 Kalams
series of treatment interruptions sparked interest in this approach as a therapeutic
modality. This subject was initially treated with HAART early after acute infection, but
an intercurrent illness prompted discontinuation of antiretroviral medications. This was
followed by a rise in viremia that was controlled with the reinstitution of HAART.
However, subsequent discontinuations of therapy did not result in rebound viremia, and
after 24 months off therapy this subject had viral load values persistently below 1000
copies/mL. This control of viremia was associated with persistent and vigorous
T-helper cell and CTL responses (99). Another report describing augmented immune
responses in subjects with intermittent adherence to HAART also concluded that some
subjects were able to control viremia (100).
The philosophy behind this approach in individuals treated early after acute infection
is that these subjects tend to have preserved helper T-cell responses (43), a feature
typically seen only in chronically infected subjects with control of viremia (sometimes
referred to as long-term nonprogressors) (44). The first study of treatment interruptions
in this cohort of individuals showed control of viremia (�5000 copies/mL) in 5/9 individuals
(101). Evaluation of the immune responses in this cohort of subjects demonstrated
augmented helper responses and an increase in the breadth and magnitude of
HIV-specific CTL responses over the course of treatment interruptions (66). This study
required the reinstitution of antiretroviral therapy at defined times depending on the
measured level of viremia. In a subsequent study in SIV-infected macaques, fixed intervals
of treatment interruption led to similar control of viremia (102), which would
potentially make this approach more feasible in a clinical setting. These data would
indicate that all persons with acute or early HIV infection should be considered for
treatment with HAART, either for consideration of treatment interruptions, or to
increase the likelihood that preserved immune responses would increase the effectiveness
of immunotherapy regimens. Although a survival benefit has not yet been shown,
the low level of steady-state viremia after successful structured treatment interruptions
would predict enhanced survival (103,104).
Despite the success of this approach in acutely infected subjects, efforts to replicate
these results in chronically infected subjects have not met with great success (105,106).
One major difference in this approach in chronically infected subjects is that helper
responses are not usually augmented, and even though naive cells can be generated, the
dramatic suppression of HIV in the presence of HAART may not allow these cells to
become immunologically active (76). Furthermore, the virus becomes extremely diverse
over the course of infection (66), so treatment interruptions could be less effective if a
substantial proportion of the quasispecies has escaped immune recognition. Finally, a
potential pitfall of this approach is the emergence of drug resistance owing to exposure
to suboptimal drug concentrations during the treatment interruptions, which is another
reason that such studies should be carried out under carefully controlled conditions.
Therapeutic Vaccination
The prospect of reconstituting specific immune responses with therapeutic vaccines
holds a great deal of appeal, but the results of early trials have been disappointing. This
is perhaps not surprising since several trials were initiated in the pre-HAART era. HIV
infection is associated with immune activation, as is infection with most viral agents.
However, HIV is unique in that the very T-cells that are activated to respond to the