Immunotherapy for Infectious Diseases

Active Immunization for HIV Infection 187
apeutic vaccination, cytokine infusions, and various combinations of these. No consistent
clinical benefit was found, which was directly related to the inability to control
viremia. The prospects for immune reconstitution are more realistic with the advent of
HAART, and these approaches can now be viewed from a fresh perspective.
Nonspecific Immunotherapy
Although efforts to augment immune responses are covered elsewhere in other chapters,
they may play a role in combination with HIV-specific immunotherapies, so they
will be briefly reviewed here. Since one of the major functions of T-lymphocytes is to
secrete cytokines, these were natural areas of investigation after the immune deficits
associated with AIDS were described. One of the most extensively studied immunebased
therapies in HIV-infected persons has been interleukin-2 (IL-2). IL-2 is a cytokine
secreted by activated T-lymphocytes that regulates lymphoid proliferation and maturation.
An initial pilot study demonstrated increases in viral load caused by immune activation
associated with IL-2 infusion (92). However, in the presence of antiretroviral
therapy, CD4 cell numbers doubled in subjects with baseline CD4� T-cell numbers
greater than 300 cells/mm 3 without significant increases in viremia (93). Simpler regimens
with lower doses have led to similar increases in CD4 cell counts but with less
toxicity (94). Trials thus far have been too small to discern a clinical benefit from
increased CD4 cell numbers, but two large trials with clinical end points are now
enrolling (ESPRIT and SILCAAT) and are designed to detect a decrease in HIV disease
progression.
Although these increases in CD4� cell numbers have not yet translated to clinical
efficacy, they may provide a basis for virus-specific immunotherapy. Progressive HIV
infection is associated with a greater loss of naive CD4 cells than of memory cells. The
immune control of viral infections probably depends on a broad repertoire of virusspecific
cells, and it has been shown that HIV leads to deletion of parts of the T-cell
repertoire (54). Although IL-2 administration is associated with polyclonal increases in
both naive and memory cells in HIV-infected persons, TCR repertoire analysis has
shown that defects in the repertoire are not corrected over the short term (84). However,
if naive cells are in fact generated by IL-2 administration, HIV-specific immunogens
may allow subsets of HIV-specific T-cells to expand and may also permit mediated
control of viremia.
IL-12 is another cytokine that is beginning to be tested in clinical trials. IL-12 is predominantly
produced by activated antigen-presenting cells and has been shown to augment
HIV-specific CTL function in vitro (95–97). In combination with IL-12,
HIV-specific immunogens may be much more effective at increasing HIV-specific CTL
responses. This has been demonstrated with a DNA vaccine coexpressing IL-12 in a
murine model of protective immunity against HSV-2 (98).
Structured Treatment Interruption
One alternative to therapeutic vaccination is the use of the patient’s own virus to
stimulate virus-specific immune responses. The theory behind this approach relies on
the efficacy of current HAART regiments. The ability to achieve substantial inhibition
of viral replication allows for a controlled exposure to autologous virus after treatment
interruption. An anecdotal case of a patient who was able to control viremia after a