title: Exosomes from human immunodeficiency virus type 1 (HIV-1)-infected cells license quiescent CD4+ T lymphocytes to replicate HIV-1 through a Nef- and ADAM17-dependent mechanism.
abstract: Resting CD4+ T lymphocytes resist human immunodeficiency virus (HIV) infection. Here, we provide evidence that exosomes from HIV-1-infected cells render resting human primary CD4+ T lymphocytes permissive to HIV-1 replication. These results were obtained with transwell cocultures of HIV-1-infected cells with quiescent CD4+ T lymphocytes in the presence of inhibitors of exosome release and were confirmed using exosomes purified from supernatants of HIV-1-infected primary CD4+ T lymphocytes. We found that the expression of HIV-1 Nef in exosome-producing cells is both necessary and sufficient for cell activation as well as HIV-1 replication in target CD4+ T lymphocytes. We also identified a Nef domain important for the effects we observed, i.e., the 62EEEE65 acidic cluster domain. In addition, we observed that ADAM17, i.e., a disintegrin and metalloprotease converting pro-tumor necrosis factor alpha (TNF-α) in its mature form, associates with exosomes from HIV-1-infected cells, and plays a key role in the HIV-1 replication in quiescent CD4+ T lymphocytes. Treatment with an inhibitor of ADAM17 abolished both activation and HIV-1 replication in resting CD4+ T lymphocytes. TNF-α is the downstream effector of ADAM17 since the treatment of resting lymphocytes with anti-TNF-α antibodies blocked the HIV-1 replication. The data presented here are consistent with a model where Nef induces intercellular communication through exosomes to activate bystander quiescent CD4+ T lymphocytes, thus stimulating viral spread.
  
  
  OBJECTIVE
  Overall, our findings support the idea that HIV evolved to usurp the exosome-based intercellular communication network to favor its spread in infected hosts.
authors: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy Department of Science, University Roma Tre, Rome, Italy.
authors: Claudia
authors: C
authors: Arenaccio
authors: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
authors: Chiara
authors: C
authors: Chiozzini
authors: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors: Sandra
authors: S
authors: Columba-Cabezas
authors: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
authors: Francesco
authors: F
authors: Manfredi
authors: Department of Science, University Roma Tre, Rome, Italy.
authors: Elisabetta
authors: E
authors: Affabris
authors: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors: Andreas
authors: A
authors: Baur
authors: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy maurizio.federico@iss.it.
authors: Maurizio
authors: M
authors: Federico
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D000072198:ADAM17 Protein; D000906:Antibodies / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002450:Cell Communication; D002478:Cells, Cultured; D015194:Diffusion Chambers, Culture; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055354:Exosomes / Q000737:chemistry / Q000276:immunology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human