Cell-to-cell virus transmission is one of the most efficient mechanisms of human immunodeficiency virus (HIV) spread, requires CD4 and coreceptor expression in target cells, and may also lead to syncytium formation and cell death. Here, we show that in addition to this classical coreceptor-mediated transmission, the contact between HIV-producing cells and primary CD4 T cells lacking the appropriate coreceptor induced the uptake of HIV particles by target cells in the absence of membrane fusion or productive HIV replication. HIV uptake by CD4 T cells required cellular contacts mediated by the binding of gp120 to CD4 and intact actin cytoskeleton. HIV antigens taken up by CD4 T cells were rapidly endocytosed to trypsin-resistant compartments inducing a partial disappearance of CD4 molecules from the cell surface. Once the cellular contact was stopped, captured HIV were released as infectious particles. Electron microscopy revealed that HIV particles attached to the surface of target cells and accumulated in large (0.5-1.0 m) intracellular vesicles containing 1-14 virions, without any evidence for massive clathrin-mediated HIV endocytosis. The capture of HIV particles into trypsin-resistant compartments required the availability of the gp120 binding site of CD4 but was independent of the intracytoplasmic tail of CD4. In conclusion, we describe a novel mechanism of HIV transmission, activated by the contact of infected and uninfected primary CD4 T cells, by which HIV could exploit CD4 T cells lacking the appropriate coreceptor as an itinerant virus reservoir.For many viruses, cell-to-cell virus transmission is the most efficient mechanism of viral spread because of the extremely low infectivity of free viral particles (1). In the case of human immunodeficiency virus (HIV), 1 free viral particles are infectious but show a short life span at 37°C (2) and lower infective capacity than cell-to-cell transmission (3). This latter phenomenon is favored by the polarization of viral production in the infected cell (4) and the viral receptors and coreceptors in the target cell leading to the formation of a functional (infectious) virological synapse (5, 6). Cell-to-cell virus transmission is probably involved in the spread of HIV among different populations of CD4 ϩ cells in vivo and seems to play an essential role in sexual or vertical transmission through epithelia (7,8).The process of membrane fusion induced by the envelope glycoprotein complex of HIV is independent of pH, and therefore endocytic internalization and endosomal acidification are not required to activate HIV entry into the cytoplasm (9 -12). Instead, viral entry involves direct fusion of viral and plasma cell membrane that allows for the delivery of the viral core into the cytoplasm of target cells (13). First, HIV envelope (gp120/gp41, Env) binds to CD4 and then to a chemokine receptor (CXCR4 for X4 strains and CCR5 for R5 strains), which is used by HIV particles to activate the gp41-mediated membrane fusion.A variety of cell types such as macrophages, endot...
The expression and turnover of MHC class II-peptide complexes (pMHC-II) on the surface of dendritic cells (DCs) is essential for their ability to activate CD4 T cells efficiently. The half-life of surface pMHC-II is significantly greater in activated (mature) DCs than in resting (immature) DCs, but the molecular mechanism leading to this difference remains unknown. We now show that ubiquitination of pMHC-II by the E3 ubiquitin ligase membrane-associated RING-CH 1 (March-I) regulates surface expression, intracellular distribution, and survival of pMHC-II in DCs. DCs isolated from March-I-KO mice express very high levels of pMHC-II on the plasma membrane even before DC activation. Although ubiquitination does not affect the kinetics of pMHC-II endocytosis from the surface of DCs, the survival of pMHC-II is enhanced in DCs obtained from March-Ideficient and MHC-II ubiquitination-mutant mice. Using pMHC-IIspecific mAb, we show that immature DCs generate large amounts of pMHC-II that are remarkably stable under conditions in which pMHC-II ubiquitination is blocked. Thus, the cellular distribution and stability of surface pMHC-II in DCs is regulated by ubiquitindependent degradation of internalized pMHC-II.T he initiation of an acquired immune response requires coordinated activation of antigen-specific T cells to provide both immune cell help (in the form of cytokines secreted from CD4 T cells) and immune cell effector function (in the form of cytotoxic CD8 T-cell responses and antigen-specific antibody secretion). This cascade of events is regulated primarily by antigen-presenting cells (APCs) in peripheral tissues that take up foreign antigens, process these antigens into immunogenic peptides, and display these antigenic peptides bound to MHC class II molecules on the APC surface (1). Dendritic cells (DCs) are professional APCs that function to prime naïve T cells. In their resting (or immature) state, DCs are relatively poor stimulators of naïve T cells; however, DC activation by a variety of signals induces a DC maturation cascade that up-regulates expression of peptide-loaded MHC-II complexes (pMHC-II), costimulatory molecules, and chemokine receptors that promote DC migration to secondary lymphoid organs and efficient T-cell activation.Given the central role that pMHC-II expressed on the surface of DCs play in the initiation of immune responses, there is intense interest in understanding the mechanisms leading to immunogenic peptide loading onto MHC-II, pMHC-II transport to the cell surface, and turnover of pMHC-II in DCs. Immature DCs express relatively small amounts of specific pMHC-II on their surface after exposure to antigen (2, 3), and large amounts of MHC-II are retained in intracellular antigen-processing compartments (4). Upon activation of these cells with inflammatory cytokines or Toll-like receptor (TLR) ligands (such as LPS or dsRNA), additional pMHC-II are generated (2, 5), and these pMHC-II are "released" from intracellular stores and traffic to the plasma membrane (6). Curiously, pMHC-II that ar...
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