title: HIV-1 matrix protein p17 increases the production of proinflammatory cytokines and counteracts IL-4 activity by binding to a cellular receptor.
abstract: Purified recombinant HIV-1 p17 matrix protein significantly increased HIV-1 replication in preactivated peripheral blood mononuclear cell cultures obtained from healthy donors. Because HIV-1 infection and replication is related to cell activation and differentiation status, in the present study, we investigated the role played by p17 during the process of T cell stimulation. Using freshly isolated peripheral blood mononuclear cells, we demonstrate that p17 was able to enhance levels of tumor necrosis factor alpha and IFN-gamma released from cells stimulated by IL-2. IL-4 was found to down-regulate IFN-gamma and tumor necrosis factor alpha, and p17 restored the ability of cells to produce both cytokines. The property of p17 to increase production of proinflammatory cytokines could be a mechanism exploited by the virus to create a more suitable environment for HIV-1 infection and replication. Our data show that p17 exerts its biological activity after binding to a specific cellular receptor expressed on activated T lymphocytes. The functional p17 epitope involved in receptor binding was found to be located at the NH(2)-terminal region of viral protein. Immunization of BALB/c mice with a 14-aa synthetic peptide representative of the HIV-1 p17 functional region (SGGELDRWEKIRLR) resulted in the development of p17 neutralizing antibodies capable of blocking the interaction between p17 and its cellular receptor. Our results define a role for p17 in HIV-1 pathogenesis and contribute to our understanding of the molecular mechanism of HIV-1 infection and the development of additional antiviral therapeutic strategies.
authors.affiliation: Institute of Microbiology, University of Brescia Medical School, 25123 Brescia, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: De Francesco
authors.forename: Manuela
authors.initials: M
authors.lastname: Baronio
authors.forename: Simona
authors.initials: S
authors.lastname: Fiorentini
authors.forename: Costantino
authors.initials: C
authors.lastname: Signorini
authors.forename: Carlo
authors.initials: C
authors.lastname: Bonfanti
authors.forename: Claudio
authors.initials: C
authors.lastname: Poiesi
authors.forename: Mikulas
authors.initials: M
authors.lastname: Popovic
authors.forename: Manuela
authors.initials: M
authors.lastname: Grassi
authors.forename: Emirena
authors.initials: E
authors.lastname: Garrafa
authors.forename: Luisa
authors.initials: L
authors.lastname: Bozzo
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.forename: Stefano
authors.initials: S
authors.lastname: Licenziati
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gallo
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Caruso
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology; D015683:Gene Products, gag / Q000494:pharmacology*; D015488:HIV Antigens / Q000494:pharmacology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000276:immunology; D012016:Reference Values; D014764:Viral Proteins; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D016207:Cytokines; D015683:Gene Products, gag; D015488:HIV Antigens; D007376:Interleukin-2; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; D015847:Interleukin-4; D007371:Interferon-gamma