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*
Clincial Immunology Section, Laboratory of Clinical Investigation, and
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, and
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
§
Immunex Corporation, Seattle, WA 98101
The role of exogenous stimulation of CD40 by CD40 ligand (CD40L) in
dendritic cell (DC) maturation, CC-chemokine production, and CCR5
receptor expression was examined using a soluble trimeric CD40L
agonist protein (CD40LT). Stimulation of monocyte-derived DCs with
CD40LT enhanced the production of the CC-chemokines macrophage
inflammatory protein (MIP)-1
, MIP-1ß, and RANTES and diminished
surface expression of CCR5. Based on these findings, the functional
role of CD40LT stimulation on the ability of DCs to replicate and
transmit HIV viral infection was studied. The addition of CD40LT to
cocultures of naive CD4+ T cells and autologous DCs (T/DC)
infected with the macrophage-tropic isolate, HIVBaL, caused
a striking reduction in reverse transcriptase (RT) activity after 10
and 14 days of culture. The addition of a mixture of Abs against
CC-chemokines abrogated the decrease in RT activity, demonstrating that
the inhibitory effect mediated by CD40LT was CC-chemokine-dependent. In
contrast, the presence of CD40LT in T/DC cocultures infected with the T
cell-tropic isolate, HIVIIIB, caused an increase in RT
activity that was CC-chemokine-independent. Of note, CD40LT stimulation
also inhibited RT activity in cultures containing macrophage-tropic
virus (HIVBaL)-infected DC only. However, in contrast to
the results seen in the T/DC cocultures, CD40LT stimulation inhibited
RT activity in cultures of DCs alone in a CC-chemokine-independent
manner. Together, these results show that CD40LT stimulation of DCs
suppresses HIV replication and transmission to CD4+ T cells
by two potentially different mechanisms.
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