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,¶
* Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10021;
University of Massachusetts Medical Center, Program in Molecular Medicine, Worchester, MA 01605;
Center for Biomedical Research, The Population Council, New York, NY 10021;
Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016; and
¶ Tulane Regional Primate Research Center, Tulane University, Covington, LA 70433
Immature dendritic cells (DCs), unlike mature DCs, require the
viral determinant nef to drive immunodeficiency virus
(SIV and HIV) replication in coculture with CD4+ T cells.
Since immature DCs may capture and get infected by virus during mucosal
transmission, we hypothesized that Nef associated with the virus or
produced during early replication might modulate DCs to augment virus
dissemination. Adenovirus vectors expressing nef were
used to introduce nef into DCs in the absence of other
immunodeficiency virus determinants to examine Nef-induced changes that
might activate immature DCs to acquire properties of mature DCs and
drive virus replication. Nef expression by immature
human and macaque DCs triggered IL-6, IL-12, TNF-
, CXCL8, CCL3, and
CCL4 release, but without up-regulating costimulatory and other
molecules characteristic of mature DCs. Coincident with this,
nef-expressing immature DCs stimulated stronger
autologous CD4+ T cell responses. Both SIV and HIV
nef-expressing DCs complemented defective SIVmac239
delta nef, driving replication in autologous immature
DC-T cell cultures. In contrast, if DCs were activated after capturing
delta nef, virus growth was not exacerbated. This
highlights one way in which nef-defective virus-bearing
immature DCs that mature while migrating to draining lymph nodes could
induce stronger immune responses in the absence of overwhelming
productive infection (unlike nef-containing wild-type
virus). Therefore, Nef expressed in immature DCs signals a distinct
activation program that promotes virus replication and T cell
recruitment but without complete DC maturation, thereby lessening the
likelihood that wild-type virus-infected immature DCs would activate
virus-specific immunity, but facilitating virus
dissemination.
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