Immunotherapy for Infectious Diseases

230 Kilby and Bucy
of viral replication and an increase in general immune responsiveness (owing in part
to a change in the cytokine milieu and lymphocyte redistribution) on HAART, restimulating
HIV-specific CD4 and CD8 T cell immunity may be critical for achieving prolonged
immunologic containment of viral replication.
The most promising strategy being explored for preventive HIV vaccines is to combine
a prime immunogen (often incorporating HIV antigens within an attenuated viral
vector) with boost peptide immunogens (gp120, gp160, or portions thereof) to induce
CTL and neutralizing antibody, respectively (100,101). The ideal immunogen for therapeutic
vaccination strategies, once chronic viral infection has already been established,
may be an agent from the former category (designed to present antigens via a
class I- or CTL-mediated mechanism rather than the more conventional aim of stimulating
neutralizing antibody). Multicenter randomized clinical trials have been designed
to evaluate the effects of combining HAART with HIV therapeutic vaccinations. One
trial in development will compare the effects of different immune-based strategies
(cycles of IL-2, a canarypox HIV immunogen, or both) in addition to HAART on the
extent of virologic rebound when therapy is temporarily interrupted after 1 year.
Another intriguing line of evidence regarding the influence of host immune responses
on the viral load set point derives from observations of intermittent therapy. Generally,
adherence to combination drug regimens has been one of the tenets of HIV therapy,
and there is evidence that incomplete suppression (such as with inappropriately low
drug doses or frequently skipped doses) leads to a higher incidence of drug resistance
over time. However, individual patients who intermittently received moderately potent
but not complete suppression on the combination of didanosine and hydroxyurea, for
example, appear to maintain HIV-specific CTL responses that correlate with strikingly
delayed and attenuated viral rebound when treatment is held (102,103). Similarly, in
studies of acutely infected patients who received antiretroviral therapy very early in the
disease course, those patients who had abrupt, self-limited interruptions in HAART
tended to develop strong HIV-specific CTL responses corresponding to very limited
viral rebound on discontinuation of therapy (104). These anecdotal observations suggest
the possibility that, under the right circumstances, strategic interruptions in therapy
may result in restimulation of waning host immune responses that can mediate
control of viral replication rates after therapy becomes intolerable or is no longer effective.
Pilot studies are under way to determine the effects of different therapeutic strategies
involving experimental vaccines and planned HAART interruptions as synergistic
exogenous and endogenous immunizations, respectively.
Although complete viral eradication remains a worthy goal of HIV treatment, these
preliminary observations and studies suggest that long-term immunologic control over
HIV replication may be more eminently achievable and just as beneficial in the long
run. Analogous to other common human viral pathogens (cytomegalovirus, Epstein-
Barr virus, varicella-zoster virus, and so on) that maintain some form of clinical latency
following a temporary or subclinical illness, it is conceivable that immune-based therapies
can induce a life-long truce with HIV that falls short of a complete cure. Avoidance
of damaging high levels of viral replication without the need for costly and
complex ongoing therapies would result in a dramatic change in the natural history of
HIV infection for each infected individual and could potentially alter our perspective
on the overall AIDS epidemic.