Immunotherapy for Infectious Diseases

Dendritic Cells 101
several organisms infect DCs and/or otherwise compromise DC function and presumably
gain a significant survival advantage by doing so.
The role of DC in HIV infection and spread is controversial. A number of studies suggest
that HIV takes advantage of the antigen-presenting and lymph node-homing properties
of DCs. Thus, the initiation of most cases of HIV infection involves passage of
the virus through mucous membranes, a process that is enhanced by local tissue damage
and inflammation. DCs are believed to be the first cells to interact with HIV at these
sites (26), where they can be infected and become latent and/or persistent sources of
infectious virus (27,28). When these cells interact with CD4� T-cells, either in the
draining lymphoid organs or before migration at sites of inflammation, they can efficiently
transfer infection (28–31). Immature DCs in peripheral blood that migrate to
mucosal sites have been posited to be the initial targets of HIV-1 infection, preferentially
via R5 viruses. Freshly isolated peripheral blood DCs (DC precursors) have the
highest number of CCR5 antibody binding sites based on quantitative fluorescenceactivated
cell sorting analysis. Downregulation of CCR5 and upregulation of CXCR4
occur with maturation of DCs. Mature cells express more CXCR4 receptors and are more
susceptible to HIV R4 infection. However, different strains of HIV are often found in
DCs and T-cells purified from the blood of AIDS patients, and there is no close correlation
between infection levels in DCs and T-cells (32). These observations indicate that
many strains may not be trafficking between DCs and T-cells. Finally, the possibility
exists that myeloid and plasmacytoid DC differ in their susceptibility to HIV infection.
Despite their putative role in facilitating initial HIV infection, as APCs, DCs play
important roles in both innate and acquired immunity to HIV infection. Plasmacytoid DC
are important in innate immunity by producing IFN-� upon HIV exposure that partially
inhibit viral replication. These cells also induce Thl immunity (33,34). Myeloid DC
induce both primary and recall HIV-specific helper T-cell and CTL responses that kill
virus-infected target cells (20,35–37). There are controversial reports of defective antigen
presentation by DCs to T-cells in HIV-infected patients (38–45). Moreover, as HIVinfected
patients progress to AIDS, there is progressive deterioration in the ability to
generate functional DCs from precursors in the blood and bone marrow. Nonetheless,
CTL epitopes of HIV induce both primary and secondary immune responses (20,35), and
such epitopes are candidates for use in vaccines. Exposure of DCs to these epitopes followed
by administration of antigen-loaded DCs in vivo can also initiate primary CTL
responses (46). DCs loaded with HIV antigens can initiate both CD4� and CD8� Tcell-mediated
immune responses, which have the potential to suppress viral load (46,47).
DCs also express macrophage inflammatory protein (MIP)-1�, MIP-1�, and RANTES,
which could block virus coreceptor expression and protect otherwise susceptible cells
from infection (48,49). We have shown that DCs from HIV-infected persons with CD4�
T-cells � 400/mm 3 can induce HIV-specific CTLs in vitro (20). Most importantly, in a
recent clinical trial, infusion of HIV antigen-pulsed DCs in HIV-infected patients was
shown to be safe and immunogenic (see below and ref. 46).
DENDRITIC CELLS IN OTHER (NON-HIV) INFECTIONS
Trypanosoma cruzi, the etiologic agent of Chagas’ disease, infects humans and animals
and induces natural killer (NK) cells, T-cells, and macrophages to secrete cytokines
such as IFN-� and tumor necrosis factor-� (TNF-�), which in turn control the disease.