Immunotherapy for Infectious Diseases

156 Fox
plasma cells. Failure of this T-helper cell function leads to loss of humoral response to
the antigen against which the T-cell was primed. Similarly, cell-mediated immunity
depends on antigen display by an antigen-presenting cell (APC) such as a B-cell,
macrophage, or circulating dendritic cell, encounter with a matching receptor on a
mobilized T-cell, stimulation of the T-cell by second receptor binding and lymphokines
from the APC, and appropriate activation of the T-cell. The activated cell then secretes
lymphokines that may attract immune cells (including macrophages, granulocytes, and
other lymphocytes), stimulate the growth of T-cells, and induce killer cell activity.
Defects in any of these steps leads to failure of all the subsequent responses.
Both the number and function of CD4� T-cells is compromised by HIV infection.
Many factors seem to contribute to the fall in CD4� T-cell number, including lysis by
HIV itself, lysis by HIV-specific CTL, syncytia formation, apoptosis, and reduced rate
of T-cell synthesis (29). Sequestration in lymphoid tissue also reduces the number of
CD4� T-cells in the peripheral blood. The rate of CD4� T-cell infection is inadequate
to account for most of the cell loss, particularly early in HIV disease. Apoptosis seems
to contribute significantly to this cell loss, which affects uninfected as well as infected
cells. Many auxiliary HIV proteins, such as Nef, Tat, and Vpr, which have regulatory
functions in HIV maturation, also appear to contribute to this immune dysfunction (30).
Linking of gp120, which is shed by HIV, with CD4 can program cells for apoptosis
upon receipt of a second stimulatory signal delivered via the T-cell receptor. Thus cells
exposed to soluble HIV proteins, but uninfected by HIV, may undergo apoptosis. This
may lead to deletion of clones of memory cells at the moment they are activated by the
antigen to which they are programmed to respond.
It is not surprising, then, in the constant presence of HIV antigen, that HIV-specific
CD4� T-helper cells are rapidly depleted (31). The same mechanism may underlie the
loss of response to recall antigens, with accompanying vulnerability to other infectious
agents. Binding of HIV-induced proinflammatory cytokines with the apoptosis-inducing
CD95 or tumor necrosis factor receptor 1 (TNFR-1) receptors may also contribute to cell
death. The rate of synthesis of T-cells has been shown to be reduced by HIV infection
and to increase when HIV replication is suppressed by antiviral drugs (32). The reason
for this inhibition of T-cell synthesis is unclear, but it may involve more than one mechanism.
The maturation of thymus-derived naive T-cells is probably inhibited by effects of
HIV on both thymic epithelial cells and immature thymic precursor cells (33). The
extrathymic expansion of T-cells is inhibited by the disruption of cytokine signaling, in
particular by the reduced expression of interleukin-2 (IL-2) and the IL-2 receptor (34).
The failure of CD4� T-cell function seems to be due to disruption of the normal
cellular and intercellular signaling mechanisms. CD4� T-cell anergy can result from
inappropriate signaling after gp120 binding to CD4. Stimulation by superantigen binding
nonspecifically to the T-cell receptor may cause the massive overexpansion of
T-cell subsets and may also cause deletion of these subsets if they are already primed
for apoptosis (35). APC interaction with T-cells may fail, if the proper cytokine signal
does not accompany antigen presentation. HIV-infected monocytes/macrophages
express decreased MHC class II, CD80/86 costimulatory molecule, and IL-12 and
increased IL-10, Fas (CD-95), and Fas ligand (CD-95L). Interaction of such APCs with
CD4� T-cells predisposes to T-cell death, either through apoptosis or HIV infection