Endogenously expressed nef uncouples cytokine and chemokine production from membrane phenotypic maturation in dendritic cells.
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-alpha, 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.
Messmer
Davorka
D
Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10021, USA.
Jacqué
Jean-Marc
JM
Santisteban
Christine
C
Bristow
Cynthia
C
Han
Seol-Young
SY
Villamide-Herrera
Lorley
L
Mehlhop
Erin
E
Marx
Preston A
PA
Steinman
Ralph M
RM
Gettie
Agegnehu
A
Pope
Melissa
M
D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D005260:Female; D015693:Gene Products, nef / Q000096:biosynthesis* / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D008297:Male; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus
D018925:Chemokines; D016207:Cytokines; D015693:Gene Products, nef; D054311:nef Gene Products, Human Immunodeficiency Virus