Immunotherapy for Infectious Diseases

Immunopathogenesis of HIV Disease 155
activation state throughout most of the course of HIV disease. This produces the characteristic
reversal of CD4�/CD8� cell ratio. CD8� T-cells suppress HIV replication
through CTL activity and through noncytolytic suppressor action. Much of the latter
activity is thought to be due to production of the �-chemokines that are the natural ligands
for the second receptors utilized by HIV during binding to target cells, although
additional suppressor factors also seem to be involved (27).
Late in the course of HIV disease, the numbers of circulating CD8� T-cells fall,
heralding much more rapid disease progression. Although clinical manifestations of
HIV disease may not occur for a decade after infection, HIV replication in lymphoid
tissues continues throughout this time. The high mutation rate of the virus leads to
steady escape from immunologic containment, as well as development of resistance to
antiretroviral drugs. With progression to AIDS, the architecture of the lymphoid tissue
collapses, as both T- and B-cell regions involute and the FDC network is disrupted.
HIV previously contained in lymphoid tissue is then released, with a sharp increase in
plasma viremia.
In the absence of potent antiretroviral therapy, any condition that causes an inflammatory
immune response is likely to induce increased HIV replication in the infected
host. This has been observed with a relatively mild stimulus, such as vaccination, as well
as with the more potent stimulus of intercurrent illness, such as influenza. As the disease
progresses to AIDS, the opportunistic infections that follow may do the added damage
of driving HIV expression by the inflammatory response they provoke, in addition
to the harm the infection itself causes. Globally, infection with both HIV and tuberculosis
continues to be the most difficult public health problem complicating the HIV
epidemic (28). HIV disease progresses much more rapidly in persons infected with
tuberculosis, who are also at greater risk of harboring multidrug-resistant tuberculosis.
Chronic parasitic infections also frequently accompany HIV infection, particularly in
Africa. Successful treatment of the parasite disease has been shown to ameliorate the
course of the HIV coinfection. Coinfection at the cellular level with herpesviruses and
HIV may also directly drive HIV replication, through promotor stimulation.
Immune Dysfunctions in HIV Disease
AIDS is characterized by the progressive loss of reaction to antigenic stimulation and
vulnerability to infection. Response is first lost to recall antigen, next to alloantigen, and
finally to mitogen. In pediatric AIDS, failure to resist common bacterial infections is
frequently seen, whereas in adults, this is less common, reflecting the adult’s more
mature humoral immunity. In both populations, loss of resistance to intracellular parasites,
viruses, protozoa, fungi, and mycobacteria demonstrates impaired cell-mediated
immunity. Polyclonal B-cell activation contributes to inappropriate antibody production,
autoimmune disease, and B-cell lymphomas.
The primary target for HIV infection is the activated CD4� T-cell. The central role
of this cell type in coordinating both the humoral and cell-mediated immune response
means that physical or functional loss of these cells leads to a broad array of immune
dysfunctions. B-cells that encounter a matching antigen engulf it, digest it, and display
antigen fragments on their surface in complex with MHC molecules. A mature CD4�
T-cell with a matching receptor for the antigen and MHC display must next supply
lymphokines to allow the B-cell to multiply and mature into antibody-producing