title: HIV-1 Vpr displays natural protein-transducing properties: implications for viral pathogenesis.
abstract: The 14-kDa Vpr protein of human immunodeficiency virus type 1 (HIV-1) serves multiple functions in the retroviral life cycle, including the enhancement of viral replication in nondividing macrophages, the induction of G2 cell-cycle arrest in proliferating T lymphocytes, and the modulation of HIV-1-induced apoptosis. Extracellular Vpr has been detected in the sera and cerebral spinal fluid of HIV-infected patients. However, it is not known whether such forms of Vpr are biologically active. Vpr contains a carboxy-terminal basic amino acid rich segment stretch that is homologous to domains that mediate the energy- and receptor-independent cellular uptake of polypeptides by a process termed protein transduction. Similar functional protein-transducing domains are present in HIV-1 Tat, herpes simplex virus-1 DNA-binding protein VP22, and the Drosophila antennapedia homeotic transcription factor. We now demonstrate effective transduction of biologically active, synthetic Vpr (sVpr) as well as the Vpr-beta-galactosidase fusion protein. However, in contrast to other transducing proteins, Vpr transduction is not enhanced by protein denaturation, and Vpr's carboxy-terminal basic domain alone is not sufficient for its transduction across biological membranes. In contrast, the full-length Vpr protein effectively transduces a broad array of cells, leading to dose-dependent G2 cell-cycle arrest and apoptosis. Addition of Vpr into the extracellular medium also rescues the replication of Vpr-deficient strains of HIV-1 in human macrophage cultures. Native Vpr may thus be optimized for protein transduction, a feature that might enhance and extend the pathological effects of HIV infection.
authors.affiliation: Gladstone Institute of Virology and Immunology, San Fransisco, California 94141, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Sherman
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schubert
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Williams
authors.forename: Carlos M C
authors.initials: CM
authors.lastname: de Noronha
authors.forename: Jason F
authors.initials: JF
authors.lastname: Kreisberg
authors.forename: Peter
authors.initials: P
authors.lastname: Henklein
authors.forename: Warner C
authors.initials: WC
authors.lastname: Greene
mesh_terms: D002461:Cell Line, Transformed; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D054325:vpr Gene Products, Human Immunodeficiency Virus
chemical_list: D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus