HIV-1 Nef triggers Vav-mediated signaling pathway leading to functional and morphological differentiation of dendritic cells.
The accessory HIV-1 Nef protein plays a key role in AIDS pathogenesis. We recently demonstrated that exogenous Nef triggers phenotypic and functional differentiation of immature dendritic cells (DCs). Here we investigated whether the Nef-induced DC differentiation occurs with morphological remodeling and have focused on the interference of Nef in the signaling pathways that regulates DC maturation. We found that exogenous Nef enters immature DCs, promoting their functional and morphological differentiation. Specifically, Nef promotes interleukin (IL) -12 release, which closely fits with nuclear factor (NF) -kappaB activation. Nef induces rearrangement of actin microfilaments, leading to uropod and ruffle formation. Moreover, Nef increases the capacity of DCs to form clusters with allogeneic CD4+ T cells, improving immunological synapse formation. Searching for molecules involved in Nef-triggered signaling pathways driving the DC maturation, we found that Nef targets Vav and promotes its tyrosine phosphorylation, associated with its nucleus-to-cytoplasm redistribution. This has a direct effect on Vav guanine nucleotide exchange factor activity for the small GTPase Rac1. We hypothesize that targeting Vav, Nef modulates both early signaling events (such as cytoskeletal rearrangement) and delayed responses (such as transcriptional regulation), promoting DC differentiation. Our results highlight how Nef may enhance T lymphocyte activation, thus fostering virus dissemination, manipulating the DC arm of the immune response.
Department of Immunology, Istituto Superiore di Sanità Viale Regina Elena, 299 00161 Rome, Italy.
Maria Giovanna
MG
Quaranta
Benedetta
B
Mattioli
Francesca
F
Spadaro
Elisabetta
E
Straface
Luciana
L
Giordani
Carlo
C
Ramoni
Walter
W
Malorni
Marina
M
Viora
D008841:Actin Cytoskeleton / Q000648:ultrastructure; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000821:virology*; D015693:Gene Products, nef / Q000032:analysis / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D021122:Protein Subunits / Q000096:biosynthesis; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D018797:Cell Cycle Proteins; D015693:Gene Products, nef; D016328:NF-kappa B; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D054311:nef Gene Products, Human Immunodeficiency Virus; D018664:Interleukin-12; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein