Immunotherapy for Infectious Diseases

Immunopathogenesis of HIV Disease 157
(36). In the absence of appropriate APC signaling, CD4� T-helper function will not be
induced, leading to poor development of HIV-specific CD8� T-cell CTLs and noncytolytic
suppressor activity.
In addition to defective APC activity, HIV-infected monocytes/macrophages are also
impaired in migration, phagocytosis, oxidative burst, and tumor surveillance. This contributes
to the vulnerability to opportunistic infections and cancer seen in AIDS. These
cells also seem to play a key role in HIV spread across tissue barriers, especially during
primary infection and in infection of the central nervous system. Microglial cells
in central nervous system are of monocytic lineage and can be infected by HIV. Expression
of proinflammatory cytokines by HIV-infected microglia, as well as from invading
macrophages, seems to contribute to neurotoxicity.
In summary, the failure of the immune system to clear HIV, although it may successfully
contain the infection for many years, coupled with the central importance of the primary
target cells in regulating the immune response, leads to chronic immune activation
and immune dysregulation. Initially, the lesions in the immune repertoire are those directed
at HIV itself, especially the loss of HIV-specific CD4� T-helper cell function. Chronic
immune activation and apoptosis eventually lead to loss of cell-mediated immunity
directed against ubiquitous opportunistic agents. The chronic inflammation causes
bystander damage, leading to complications such as dementia and wasting. Successful
therapy with antiviral drugs leads to rapid clearance of HIV from the peripheral blood and
from most tissue sites. This is followed by reduced immune activation and partial restoration
of immune function (37). Although resistance to many opportunistic infections are
frequently restored by successful potent antiretroviral therapy, resistance to HIV itself
remains an illusive goal.
THERAPY
Range of Possible Therapeutic Modalities
As will be discussed in detail in the chapters that follow, a variety of strategies are
being explored in attempts to halt and reverse the immune dysfunction caused by HIV
disease. Foremost has been the use of antiviral agents to suppress HIV replication and
the use of antibiotic prophylaxis to prevent the emergence of opportunistic infections.
With the recent advent of potent antiretroviral therapy, the ability of the immune system
to recover spontaneously has been demonstrated, and the limits of this recovery
have also been seen (38–40). Other strategies being tested involve modulation of the
immune response, to reduce the excessive activation. Supplementation of cytokines
depressed by HIV disease, to restore the number and function of T-cells and monocytic
cells, may yield improved resistance to opportunistic disease, and conceivably to HIV
itself. Therapeutic vaccines and strategies of treatment interruption to deliberately permit
reexposure of the immune system to HIV antigen, in an effort to boost host immune
response to HIV, are being tried. Attempts are being made to reduce the size of the pool
of cells latently infected with HIV, or to make it more difficult for these cells to become
activated and to express HIV. Gene-based therapies are being developed to confer resistance
to HIV infection at the cellular level. As these and other therapeutic interventions
are developed, they present great challenges in clinical trial design.